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Timbercreek Trail
Quick Facts
- Type:Single Family Home
- Age:1971 to 1975
- Sq. Ft.:2,676 to 4,528Sq. Ft.
- Bedrooms:3 to 4Bedrooms
- Bathrooms:3Bathrooms
- Lot Sizes:1 - 3 acres
Homes for Sale
This neighborhood is perfect for those seeking single-family homes. The homes in Timbercreek Trail represent a wide range of time periods and styles. In general, homes in Timbercreek Trail are about $220,000 – $2,000,000 and sit on 2.75-acre lots with three bedrooms and three bathrooms. The most common type of parking is garage.
Disclaimer: School attendance zone boundaries are supplied by Maponics and are subject to change. Check with the applicable school district prior to making a decision based on these boundaries.

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The Flash just gave Ralph Dibney (Hartley Sawyer) an official insignia, which was worn by the character in the Justice League Unlimited series. Like Barry Allen (Grant Gustin), Elongated Man now has his own emblem in the Arrowverse.
Hartley Sawyer's Elongated Man has been on the show since the fourth episode of the fourth season, "Elongated Journey Into Night", when Ralph first developed his elastic abilities. At the beginning, Ralph was irresponsible and selfish, and a person who Barry didn't believe he could trust due to issues from their past. However, Barry decided to give Ralph a second chance and made him a member of Team Flash. Ralph's character has come a long way since that day, as he's grown to become one of the Flash's most reliable allies.
In The Flash season 6, episode 6, titled "License to Elongate", Barry and Joe (Jesse L. Martin) hatch a scheme to surprise Ralph by honoring him a ceremony and making him the new protector of Central City. After going on a dangerous mission connected to the Sue Dearbon case, Barry and Ralph make it out alive and save the city once again. At the end of the episode, Barry and Joe officially recognize Ralph for his accomplishments at CCPD in front of the press. Ralph is given an insignia with the letters "EM" on it, which will now be worn as a part of his "Elongated Man" costume.
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Also, the moment where Ralph receives the emblem symbolizes his transformation into a full-fledged superhero. It goes to show that Ralph has evolved into the hero from the comics, even though The Flash is still building toward his biggest story. Regardless, Barry has accepted Elongated Man as the hero that Central City needs, which is an important step for Team Flash. While Barry has chosen Cisco (Carlos Valdez) to be the new leader, it's Elongated Man who he wants to watch over the city after Barry dies in the Crisis. Whether or not this will happen may depend on both the Crisis and the outcome of his encounter with Ramsey (Sendil Ramamurthy) in the closing seconds of the episode.
More: The Flash Confirms Another One Of Barry Allen's Weaknesses


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Catholic Young Adults, men and women in their 20's & 30's, you are invited to join the Citywide Catholic Young Adults' Christmas Party!
When: Saturday, December 14, 2019
6:00pm to 9:00pm (or later!)
Where: Columbia Club (Knights of Columbus Hall) 2216 Grand Ave.
What: Food will be provided by St. Pius X Young Adults, no-host beverages available. There will be games, great food and more!
Please feel free to bring a friend! This is an Adults-0nly party, thank you.
Advent & Christmas Mass Schedule
Dec 24 Christmas Eve – Masses 4:00pm, 6:30pm, 9:00pm
Dec. 25 Christmas Day – Mass 10am
Jan. 1 New Year's Day Solemnity of Mary, the Holy Mother of God Holy Day of Obligation – Mass 10 am
December 10 Tuesday St. Patrick Co-Cathedral 7:00 pm
December 11 Wednesday Mary, Queen of Peace (Little Flower) 11:00 am
December 18, Wednesday St. Bernard's Parish 7:00 pm
December 19, Thursday St. Pius X (West-side Service) 7:00 pm
The Billings Vocal Ensemble, Con Spirito, presents "Adventure into Wonderland" The concerts will be held at St. Pius X Catholic Church on Saturday, November 23 at 7:00pm and on Sunday, November 24, at 3:00pm. The varied program transports the audience into the world of fantasy and the miracle of Christmas. Con Spirito (meaning "with spirit") is celebrating its 16th year as a vocal ensemble. Current members of the group are Sopranos: Rosalie Foster, Lesley Jorden, and Janie Sutton. Mezzo Sopranos: Julie Bishop, Jennine Budge, and Megan Carling. Altos: Kathleen Cochrane, Nancy Downing, and Bonnie Warne. Piano accompaniment will be provided by Caroline Peters with Sara and Dan Charney on percussion. The concert is free and we hope you will attend!
Are you staying here for Christmas? I would encourage your child or children to be in the Christmas choir! There are three practices the kids, students preschool through 8th grade, need to attend before helping with this important ministry at the Christmas Eve Mass (4:00 pm Mass time). The practices last from 5:15-6:15 pm in the Church and the dates are as follows:
December 4th
December 11th
December 18th
If interested in the choir, please come to the first practice starting on December 4th! Students MUST plan to attend all 3 rehearsals.
Jessie, Children's Ministry
Joan, Music Director


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From Third World to First: Singapore and the Asian Economic Boom EPUB ebook download link. By Author: Lee Kuan Yew. Download Links. Have not added any EPUB format description on From Third World to First: The Singapore Story:! download this book right now! 22 This student edition of. ((DOWNLOAD)) EPUB From Third World to First (Singapore and the Asian economic boom) EBOOK EPUB KINDLE PDF For download this.
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In This Review
The amount of parts per million of copper released in the Pandu before it even reaches the Ganga is a thousand times higher than in uncontaminated water. Although a relatively low proportion, they are a cause for major concern because they are often toxic and non-biodegradable. Some materials like food, waste or leaves are left in the Ganga which are also responsible for its pollution.
Traditional beliefs hold that being cremated on its banks and to float down the Ganga will atone for the sins of those who die and carry them directly to salvation. In Varanasi alone, an estimated forty thousand bodies are cremated every year, many of which are only half-burnt.
The singapore story epub torrent
Bangladesh is actively considering to construct Ganges Barrage Project for mitigating the salinity problem. Most of the water available at the upstream of the Kanpur barrage is used during dry season for the cities drinking water needs. Refer to Google Earth maps These lift irrigation schemes are pumping out most of the base flows available in the main river down stream of Kanpur city.
In addition, a series of cascading barrage cum bridges are to be constructed across the river from Kanpur to Allahabad to increase the surface area of impounded polluted water in the river so that it serves as vast natural oxidation ponds.
Coliform bacteria levels in the Ganges have also been tested to be at 5,, a level too high to be safe for agricultural use let alone drinking and bathing. Effectively, chromium levels have not decreased in the Ganges even after a common treatment plant was established in It now stands at more than 70 times the recommended maximum level. A strong positive correlation between mercury levels in muscle with food habit and fish length was found.
Listed as an endangered species, their population is believed to be less than Hydroelectric and irrigation dams along the Ganges that prevents the dolphins from travelling up and down river is the main reason for their reducing population. This turtle inhabits deep rivers, streams, large canals, lakes and ponds, with a bed of mud or sand. According to the International Union for Conservation of Nature, freshwater turtle species are vulnerable.
Due to their long lifespan and high trophic level in the aquatic food web, turtles are vulnerable to heavy metals pollution, a major kind of pollution in the Ganges.
Singh, a paediatrician at Varanasi Shiv Prasad Gupta Hospital , their parents rarely mention that they have been swimming in the river. They don't appear to have made the connection, he says. After a long struggle, British India agreed on 5 November that the uninterrupted flow of the Ganges is the rudimentary right of Hindu believers.
The day is known as a 'Aviral Ganga Samjhauta Divas' Uninterrupted Ganga flow agreement day in the history of India and the agreement came into existence on 19 December which is known as Agreement of The sanctity of the agreement is not preserved by the state and central governments of India after independence though it is legally valid.
More and more river water is diverted for irrigation use converting the river into a polluted sewer.The ultimate objective of the GAP is to have an approach of integrated river basin management considering the various dynamic interactions between abiotic and biotic eco-system. When I heave open the hard bound book that is the second volume of your memoirs, I feel as if I have been transported back in time to post-colonial Singapore. A strong positive correlation between mercury levels in muscle with food habit and fish length was found.
These are available in ePUB format. And with those eReaders comes fantastic eBook stores for easy browsing and purchasing.


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JENDELA DI BALI near UBUD | "An astonishing adventure" "A Hollywood set" | *****
- Villa2368 sq. ft.
- Sleeps: 4
- Bedrooms: 2
- Bathrooms: 3
- Half Baths: 1
- Min Stay: 2 nights
A Village Of Romantic Living Spaces in the Hills Near Ubud: "Astonishing!"
Property Manager
Our Reservation Managers at Individual Bali Hospitality
- Languages:
- english, indonesian
About Our Reservation Managers at Individual Bali Hospitality
The owners created this property by hand over 10 years, working with Balinese artisans and craftspeople to create a 'village' of unique living spaces. They are passionate about traditional architecture, arts, tropical gardens and the local culinary flavours. Their goal was to create a window on Bali, which is expressed in the name 'Jendela di Bali'. The real story is not the owners but our wonderful staff (Dayu Made and Suertini, pictured, and their team) who live in the local village and whose languid pace of life revolves around devotion to their gods and sharing their culture with you.
Why Our Reservation Managers at Individual Bali Hospitality chose Gianyar Sub-District
The owners wanted to create a secluded hideaway that was close enough to Ubud for coffee and cake, dining, dance performances, galleries and more - yet far enough away to be a real retreat from other tourists. The goal was to find a place that would allow our friends, family and guests to discover the genuine Balinese way of life. Our beautiful staff lovingly prepare a menu of simple but delicious Balinese and Indonesian-inspired meals for guests. Unlike many villas, we can offer all meals (breakfast is included in the rate and a menu offers lunch and dinner selections at a modest additional cost). We understand your desire to enjoy local flavours adjusted to western taste as well as the importance of quality and cleanliness in the fresh foods we present. We can cater in a modest and understanding way to special dietary needs, including gluten free and vegetarian cuisine with advance notice.
What makes this Villa unique
The highlights are being located along a beautiful gorge for nature, near a sacred village for the insights into the religion, near to Ubud for indulgence and entertainment and set in the heart of Bali near some of the island's most significant and holy temples and relic sites. Most important to us however is how real and genuine the setting is - this is not a tourist enclave, it is not a hushed monastery, this is genuine rural Balinese life with all its sights, sounds, activity. We like to say Jendela di Bali is 'a place in the heart of Bali to discover Bali's heart'. We hope you'll join us and let our wonderful staff pamper you and share a little of their culture with you.
- Swimming pool
- Internet
- Satellite or cable
- Children Welcome
- Parking
- No Smoking
- Bathrooms: 3, Half Baths: 1
House Rules
Check-in: 2:00 PM
Check-out: 12:00 PM
No parties/events
No smoking
No pets
Children allowed
Children over 8 years - under 8 please enquire
Minimum age of primary renter:20
Max guests:4 (sleeps up to 4 adults)
Cancellation Policy
100% refund if canceled at least 60 days before arrival date. 50% refund if canceled at least 30 days before arrival date.
3 Reviews
Gorgeous property with wonderful hosts
This property is stunning! Totally private with well manicured gardens. The sleeping bales with so cool , you felt like you were in the jungle but with all the hotel amenities. The sounds of the birds and animals were so peaceful. The pool was beautiful, a tad cold but well kept. The best part about our stay was Dayu Made and her team. Truly wonderful, caring people. They were so helpful and wanted to please. Her cooking was outstanding and the service was excellent. Our driver was also warm and so helpful. All of them truly made our experience more special, they treated us like family! Would love to come back! Thank you!!
Dear Holly and Jace,
Thank you for your wonderful feedback and we are delighted you enjoyed the very peaceful setting and service from Dayu Made and her team.
Our aim at Jendela di Bali is to give our guests a very natural and authentic Balinese experience in a lush setting and we are so pleased you enjoyed the experience.
You are family now and we look forward to having you stay at Jendela di Bali again soon!
Warmest regards, Dayu Made and her team at Jendela di Bali.
A beautiful surrounding with excelent staff
A really beautiful surrounding with verry friendly and excelent staff that made us feal right at home.
They were really good chefs with excellent meals. Specialy liked the Ginger chicken !
Even the hired drivers were friendly and helpfull with info and tips over Bali.
One remark has to been made, because due to traffic and infra structure it is always a long drive to get where ever you want to go!
A special thanks to Agus from the booking office,with getting our lost luggage back on time after some difficulties with the Airline.
I would recomment this beautiful plece to everyone !
With love and greatings to Dayu and Seuatine!
Maya, Frank ,Lion and Edwin
Dear Maya, Frank, Lion and Edwin
We are so delighted you enjoyed your stay at Jendela di Bali and that you enjoyed the wonderful home cooking by Dayu Made and Sueatini. They send their love to your family and we look forward to seeing you back again soon.
Warm regards, the team at Jendela di Bali
merveilleux !!
une villa de rêve dans un cadre sublime loin de toute agitation touristique . Et un personnel d'une extrême gentillesse se dévouant sans cesse pour aller au devant de tous nos souhaits . Nous avons quitté Jendela avec beaucoup de regret mais vraiment ravis d'avoir vécu ces 11 jours dans ce havre de paix ..
Many thanks !!!
Dear André,
It was a pleasure having you as our guests! Thank you for your wonderful review - we are delighted. Next time you are coming to Ubud Bali and looking for Ubud accommodation, it would be our pleasure to have you as our guests again.
Warm regards from Bali,
Dayu Made and all the staff at Jendela di Bali.
And for those who might like to read Andre's review in English:
"A dream villa in a beautiful setting away from tourist crowds. And staff extremely kind, devoting themselves tirelessly to reach out to all our wishes. We left Jendela di Bali with regret but really pleased to have lived these 11 days in this haven of peace...Many thanks !!!"
Our location is a highlight of Jendela di Bali because we strike the perfect balance of being away from tourist hotspots, but close enough to visit Ubud for dining, coffee and cake, art galleries, dance performances and shopping.
For a comprehensive guide to the sacred sites, attractions and activities near Jendela di Bali please click the 'Contact Manager' link and request a copy and we'll send it to you.
THE WORLD HERITAGE LISTED PAKERISAN RIVER (5 mins) - Discover a world heritage gem and see Balinese worship and enjoy this fast-flowing river.
WHITE WATER RAFTING (15 mins) - Join a tour and enjoy the thrill and adventure of rafting the Pakerisan River.
GIANYAR NIGHT MARKET (15 mins) - Discover the flavours and colours of this renowned traditional night market.
UBUD VILLAGE (30 to 45 mins) - For shopping, dining, dance performances, art galleries and more.
Goa Rang Reng Waterfall and Cave (15 mins) - Bali has many waterfalls but this is a best-kept secret, with rapids formed by two rivers and a sacred cave to explore.
TIRTA EMPUL SACRED WATER TEMPLE, Tampaksiring (15 mins) - Tirta Empul Temple is one of the important Hindu temples located in the middle of Bali. Tirtha Empul Temple was constructed during the rules of Candra Bayangsingha King of Warmadewa dynasty in 926 AD. The temple is a popular sacred destination where Hindu Bali people visit for purification rituals. According to a popular Balinese legend, the sacred water spring in the temple was created by Lord Indra and the waters have curative properties.
GUNUNG KAWI, Tampaksiring (15 mins) - Gunung Kawi is an 11th-century temple complex in Tampaksiring north east of Ubud in Bali, Indonesia. It is located near the river Pakerisan. The complex comprises 10 rock-cut candi (shrines) carved into the cliff face. They stand in 7-metre-high (23 ft) sheltered niches cut into the sheer cliff face. These monuments are thought to be dedicated to King Anak Wungsu of the Udayana dynasty and his favourite queens.
GUNUNG KAWI TEMPLE, Sebatu (25mins) - Not to be confused with Gunung Kawi, The Gunung Kawi Sebatu is a water temple built in homage to the God Wisnu (the preserver' who rules over water) and here one finds a number of natural spring and waterspouts and a wonderful pond with Koi. The Balinese believe that water is one of the forces of life. The etymology of Gunung Kawi means a fabricated mountain. It lies west of Sebatu village, which is elevated and its name means 'slipping on a stone'.
TEGALALANG RICE TERRACES - spectacular rice paddy views - a must see. Beautiful rice paddies views, terracing down deep slopes, seen from a spectacular vantage points. Great place to lunch on an alternative way in to Ubud. (30mins)
GOA GAJAH (Elephant Cave) (25 mins) - At the façade of this fascinating cave is a relief of various menacing creatures and demons carved right into the rock at the cave entrance. The primary figure was once thought to be an elephant, hence the nickname Elephant Cave. The site is mentioned in the Javanese poem Desawarnana written in 1365. An extensive bathing place on the site was not excavated until the 1950s. These appear to have been built to ward off evil spirits.
YEH PULU (25 mins) - Wonderful and sacred temple relief rock carvings discovered only very recently and dating from the 14th or 15th century showing a mix of Wayang Kulit (shadow puppet) figures and common people.
TAMAN SAFARI & MARINE PARK (25 mins) - This is a credible and respected safari and marine park.
TAMAN NUSA ARCHITECTURE CULTURAL PARK (25 mins) - For those interested in traditional architecture of Indonesia this park is a must-visit.
MOUNT BATUR VOLCANO, Kintamani (35 mins) - Experience the awe of an active volcano. Caldera trekking tours are available or simply drive into the caldera and discover lakeside villages.
ELEPHANT SAFARI PARK, Taro (35 mins) - Renowned for its conservation work with Elephants
BALI BIRD PARK (40 mins) - A beautiful parkland garden setting with lakes and a stunning collection of birds including the rare Bali Starling.
We are closer to many of the above attractions than staying in Ubud or down south and there are many more places of cultural and religious significance too numerous to mention, all within easy reach of Jendela di Bali.
All of the above can be easily reached with arranging a car + driver hire, which we recommend to all guests. Jendela di Bali is managed by Individual Bali Hospitality who can arrange car and driver hire and tours for guests.
Sources: Wikipedia, WikiTravel


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Bulls Head
Open today until 11:00 PM
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Discover The Bulls Head
Let yourself relax at the Bulls Head in Kings Norton. We serve great quality food that is amazing value, so treat night can be every night! With daily offers and our brilliant light bites, you can enjoy delicious pub classics without worrying about the bill.
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Wednesday 11 December 2019
A NEW initiative, Singing for Syrians, is urging communities in Britain to organise fund-raising carol concerts for refugees in the Middle East.
Singing for Syrians is being promoted by Christian Aid and the Hands Up Foundation to support refugee camps in the region. Concert organisers will be invited to a carol concert in St Margaret's, beside Westminster Abbey, on 15 December, and to a private reception at Speaker's House.
The initiative has been organised by a trustee of the Hands Up Foundation, the artist George Butler, and the Conservative MP for North Oxfordshire, Victoria Prentis, and is championed by Basil Eastwood, a former British ambassador to Syria.
"Before I was elected," Mrs Prentis said, "I found that carol concerts were a great way to raise money while having a good sing. It therefore seemed obvious to me that concerts would be a good way to raise money for the most desperate people who remain in Syria.
"Whether they pass around a bucket at a planned carol concert or come to the St Margaret's concert on 15 December, I really hope people will get behind this initiative."
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21-22 February 2020Church Times Festival of Faith and LiteratureWith Sam Wells, Catherine Fox, Mark Oakley, Suzannah Lipscomb and many others. See the full programme
26 March 2020Theology Slam Live FinalTheology Slam is back, continuing its search for the most engaging young voices on theology and the contemporary world. Find out more
King's College has a rich tradition and future focus that supports students and the King's community to realise the best all round education there is. An outstanding opportunity has arisen to become the Senior Chaplain for the College commencing in 2020.
The successful candidate would enhance the worshipping life and outreach of a community accustomed to a high standard of traditional music. But we have a wide spectrum of worship needs so the director would also be willing to explore informal/contemporary music styles.
The Bishop of Chichester is seeking to appoint a Priest-in-Charge (House for Duty) for the Parish of St Mary's, Chidham.
We invite you to apply for this delightful part time (15% stipend – 2 days plus Sunday) post.
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Five hundred years after the death of Leonardo da Vinci, Caroline Levisse looks at a celebrated and often parodied masterpiece
In the run-up to the General Election, Church Times and Christian Aid asked Boris Johnson, Jeremy Corbyn, and Jo Swinson to write exclusively on their policy priorities
To explore the Church Times website fully, please sign in or subscribe.
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Single Family Detached
- 3 beds
- 2 baths
- $449,900 price
- 3591104 mls id
- Year Built: 1952
Opportunity knocks! Beautiful property ~ Tons of potential and many options. Beautiful property on the corner of Wyoming ~ Minutes to Watchung Stables and Reservation ~ Get off the train and you're home in paradise in minutes ~ Take advantage of the Mountainside School System ~ Best value in Mountainside.
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Single Family Detached
23 Pictures
Well Maintained Ranch on a Corner Lot, 3 Bedrooms, 1.5 Bathrooms, Living Room/Dining Room Combo with Wood Burning Fireplace, Eat in Kitchen with access to a Heated Sun Porch, Unfinished Basement and Attached One Car Garage. Beautiful Backyard with endless possibilities. Easy access to major...
271 Summit Rd Mountainside Boro, NJ
3 beds, 2 baths, $444,900
Courtesy of: Union Office
Office Phone: +19086883000
Listing Agent: Arlyne Mirro
Updated: 8th December, 2019 8:55 AM.
351 Summit Rd Mountainside Boro, NJ


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The diagnostic yield of exome and genome sequencing remains low (8-70%), due to incomplete knowledge on the genes that cause disease. To improve this, we use RNA-seq data from 31,499 samples to predict which genes cause specific disease phenotypes, and develop GeneNetwork Assisted Diagnostic Optimization (GADO). We show that this unbiased method, which does not rely upon specific knowledge on individual genes, is effective in both identifying previously unknown disease gene associations, and flagging genes that have previously been incorrectly implicated in disease. GADO can be run on www.genenetwork.nl by supplying HPO-terms and a list of genes that contain candidate variants. Finally, applying GADO to a cohort of 61 patients for whom exome-sequencing analysis had not resulted in a genetic diagnosis, yields likely causative genes for ten cases.
AssuntosRegulação da Expressão Gênica/fisiologia , Predisposição Genética para Doença , Análise de Sequência de RNA/métodos , Transcriptoma , Bases de Dados de Ácidos Nucleicos , Humanos , Modelos Genéticos , Análise de Componente Principal , Software , Interface Usuário-Computador
BACKGROUND: Growth retardation is one of the main hallmarks of CHARGE syndrome (CS), yet little is known about the body proportions of these children. Knowledge of body proportions in CS may contribute to a better characterization of this syndrome. This knowledge is important when considering starting growth-stimulating therapy. METHODS: For this cross-sectional study, we selected 32 children with CS and a CHD7 mutation at the Dutch CHARGE Family Day in 2016 or 2017 and the International CHARGE conference in Orlando, Florida, in 2017. We used photogrammetric anthropometry-a measurement method based on digital photographs-to determine various body proportions. We compared these to measurements in 21 normally proportioned children with growth hormone deficiency, using independent-samples t test, Mann-Whitney U test, or chi-square test as appropriate. RESULTS: Children with CS appear to have a shorter trunk in proportion to their height, head length, and arm length. Children with CS also had smaller feet proportional to tibia length compared to controls. The change of body proportions with age was similar in children with CS and controls. CONCLUSION: Body proportions in children with CS are significantly different from those of normally proportioned controls, but a similar change of body proportions with age was noted for both groups.
Alterations of the N-methyl-d-aspartate receptor (NMDAR) subunit GluN2A, encoded by GRIN2A, have been associated with a spectrum of neurodevelopmental disorders with prominent speech-related features, and epilepsy. We performed a comprehensive assessment of phenotypes with a standardized questionnaire in 92 previously unreported individuals with GRIN2A-related disorders. Applying the criteria of the American College of Medical Genetics and Genomics to all published variants yielded 156 additional cases with pathogenic or likely pathogenic variants in GRIN2A, resulting in a total of 248 individuals. The phenotypic spectrum ranged from normal or near-normal development with mild epilepsy and speech delay/apraxia to severe developmental and epileptic encephalopathy, often within the epilepsy-aphasia spectrum. We found that pathogenic missense variants in transmembrane and linker domains (misTMD+Linker) were associated with severe developmental phenotypes, whereas missense variants within amino terminal or ligand-binding domains (misATD+LBD) and null variants led to less severe developmental phenotypes, which we confirmed in a discovery (P = 10-6) as well as validation cohort (P = 0.0003). Other phenotypes such as MRI abnormalities and epilepsy types were also significantly different between the two groups. Notably, this was paralleled by electrophysiology data, where misTMD+Linker predominantly led to NMDAR gain-of-function, while misATD+LBD exclusively caused NMDAR loss-of-function. With respect to null variants, we show that Grin2a+/- cortical rat neurons also had reduced NMDAR function and there was no evidence of previously postulated compensatory overexpression of GluN2B. We demonstrate that null variants and misATD+LBD of GRIN2A do not only share the same clinical spectrum (i.e. milder phenotypes), but also result in similar electrophysiological consequences (loss-of-function) opposing those of misTMD+Linker (severe phenotypes; predominantly gain-of-function). This new pathomechanistic model may ultimately help in predicting phenotype severity as well as eligibility for potential precision medicine approaches in GRIN2A-related disorders.
AssuntosEpilepsia/genética , Transtornos do Neurodesenvolvimento/genética , Receptores de N-Metil-D-Aspartato/genética , Adolescente , Adulto , Idoso , Animais , Células Cultivadas , Córtex Cerebelar/metabolismo , Criança , Pré-Escolar , Epilepsia/fisiopatologia , Feminino , Genótipo , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação , Transtornos do Neurodesenvolvimento/fisiopatologia , Fenótipo , Ratos , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/fisiologia , Adulto Jovem
OBJECTIVE: To delineate the epileptology, a key part of the SYNGAP1 phenotypic spectrum, in a large patient cohort. METHODS: Patients were recruited via investigators' practices or social media. We included patients with (likely) pathogenic SYNGAP1 variants or chromosome 6p21.32 microdeletions incorporating SYNGAP1. We analyzed patients' phenotypes using a standardized epilepsy questionnaire, medical records, EEG, MRI, and seizure videos. RESULTS: We included 57 patients (53% male, median age 8 years) with SYNGAP1 mutations (n = 53) or microdeletions (n = 4). Of the 57 patients, 56 had epilepsy: generalized in 55, with focal seizures in 7 and infantile spasms in 1. Median seizure onset age was 2 years. A novel type of drop attack was identified comprising eyelid myoclonia evolving to a myoclonic-atonic (n = 5) or atonic (n = 8) seizure. Seizure types included eyelid myoclonia with absences (65%), myoclonic seizures (34%), atypical (20%) and typical (18%) absences, and atonic seizures (14%), triggered by eating in 25%. Developmental delay preceded seizure onset in 54 of 56 (96%) patients for whom early developmental history was available. Developmental plateauing or regression occurred with seizures in 56 in the context of a developmental and epileptic encephalopathy (DEE). Fifty-five of 57 patients had intellectual disability, which was moderate to severe in 50. Other common features included behavioral problems (73%); high pain threshold (72%); eating problems, including oral aversion (68%); hypotonia (67%); sleeping problems (62%); autism spectrum disorder (54%); and ataxia or gait abnormalities (51%). CONCLUSIONS: SYNGAP1 mutations cause a generalized DEE with a distinctive syndrome combining epilepsy with eyelid myoclonia with absences and myoclonic-atonic seizures, as well as a predilection to seizures triggered by eating.
AssuntosDeficiências do Desenvolvimento/genética , Mutação/genética , Espasmos Infantis/genética , Proteínas Ativadoras de ras GTPase/genética , Adolescente , Adulto , Anticonvulsivantes/uso terapêutico , Encéfalo/diagnóstico por imagem , Encefalopatias/complicações , Encefalopatias/diagnóstico por imagem , Encefalopatias/genética , Criança , Pré-Escolar , Estudos de Coortes , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/diagnóstico por imagem , Eletroencefalografia , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Espasmos Infantis/complicações , Espasmos Infantis/diagnóstico por imagem , Espasmos Infantis/tratamento farmacológico , Adulto Jovem
We studied the presence of benign infantile epilepsy (BIE), paroxysmal kinesigenic dyskinesia (PKD), and PKD with infantile convulsions (PKD/IC) in patients with a 16p11.2 deletion including PRRT2 or with a PRRT2 loss-of-function sequence variant. Index patients were recruited from seven Dutch university hospitals. The presence of BIE, PKD and PKD/IC was retrospectively evaluated using questionnaires and medical records. We included 33 patients with a 16p11.2 deletion: three (9%) had BIE, none had PKD or PKD/IC. Twelve patients had a PRRT2 sequence variant: BIE was present in four (pâ¯=â¯0.069), PKD in six (pâ¯<â¯0.001) and PKD/IC in two (pâ¯=â¯0.067). Most patients with a deletion had undergone genetic testing because of developmental problems (87%), whereas all patients with a sequence variant were tested because of a movement disorder (55%) or epilepsy (45%). BIE, PKD and PKD/IC clearly showed incomplete penetrance in patients with 16p11.2 deletions, but were found in all and 95% of patients with a PRRT2 sequence variant in our study and a large literature cohort, respectively. Deletions and sequence variants have the same underlying loss-of-function disease mechanism. Thus, differences in ascertainment have led to overestimating the frequency of BIE, PKD and PKD/IC in patients with a PRRT2 sequence variant. This has important implications for counseling if genome-wide sequencing shows such variants in patients not presenting the PRRT2-related phenotypes.
Proximal 6q (6q11-q15) deletions are extremely rare and little is known about their phenotypic consequences. Since parents and caregivers now use social media to seek information on rare disorders, the Chromosome 6 Project has successfully collaborated with a Facebook group to collect data on individuals worldwide. Here we describe a cohort of 20 newly identified individuals and 25 literature cases with a proximal 6q deletion. Microarray results and phenotype data were reported directly by parents via a multilingual online questionnaire. This led to phenotype descriptions for five subregions of proximal 6q deletions; comparing the subgroups revealed that 6q11q14.1 deletions presented less severe clinical characteristics than 6q14.2q15 deletions. Gastroesophageal reflux, tracheo/laryngo/bronchomalacia, congenital heart defects, cerebral defects, seizures, and vision and respiratory problems were predominant in those with 6q14.2q15 deletions. Problems related to connective tissue (hypermobility, hernias and foot deformities) were predominantly seen in deletions including the COL12A1 gene (6q13). Congenital heart defects could be linked to deletions of MAP3K7 (6q15) or TBX18 (6q14.3). We further discuss the role of ten genes known or assumed to be related to developmental delay and/or autism (BAI3, RIMS1, KCNQ5, HTR1B, PHIP, SYNCRIP, HTR1E, ZNF292, AKIRIN2 and EPHA7). The most influential gene on the neurodevelopmental phenotype seems to be SYNCRIP (6q14.3), while deletions that include more than two of these genes led to more severe developmental delay. We demonstrate that approaching individuals via social media and collecting data directly from parents is a successful strategy, resulting in better information to counsel families.
CHARGE syndrome is an autosomal dominant malformation disorder caused by heterozygous loss of function mutations in the chromatin remodeler CHD7. Chd7 regulates the expression of Sema3a, which also contributes to the pathogenesis of Kallmann syndrome, a heterogeneous condition with the typical features hypogonadotropic hypogonadism and an impaired sense of smell. Both features are common in CHARGE syndrome suggesting that SEMA3A may provide a genetic link between these syndromes. Indeed, we find evidence that SEMA3A plays a role in the pathogenesis of CHARGE syndrome. First, Chd7 is enriched at the Sema3a promotor in neural crest cells and loss of function of Chd7 inhibits Sema3a expression. Second, using a Xenopus CHARGE model, we show that human SEMA3A rescues Chd7 loss of function. Third, to elucidate if SEMA3A mutations in addition to CHD7 mutations also contribute to the severity of the CHARGE phenotype, we screened 31 CHD7-positive patients and identified one patient with a heterozygous non-synonymous SEMA3A variant, c.2002A>G (p.I668V). By analyzing protein expression and processing, we did not observe any differences of the p.I668V variant compared with wild-type SEMA3A, while a pathogenic SEMA3A variant p.R66W recently described in a patient with Kallmann syndrome did affect protein secretion. Furthermore, the p.I668V variant, but not the pathogenic p.R66W variant, rescues Chd7 loss of function in Xenopus, indicating that the p.I668V variant is likely benign. Thus, SEMA3A is part of an epigenetic loop that plays a role in the pathogenesis of CHARGE syndrome, however, it seems not to act as a common direct modifier.
"CHARGE syndrome" is a complex syndrome with high and extremely variable comorbidity. As a result, clinicians may struggle to provide accurate and comprehensive care, and this has led to the publication of several clinical surveillance guidelines and recommendations for CHARGE syndrome, based on both single case observations and cohort studies. Here we perform a structured literature review to examine all the existing advice. Our findings provide additional support for the validity of the recently published Trider checklist. We also identified a gap in literature when reviewing all guidelines and recommendations, and we propose a guideline for neuroradiological evaluation of patients with CHARGE syndrome. This is of importance, as patients with CHARGE are at risk for peri-anesthetic complications, making recurrent imaging procedures under anesthesia a particular risk in clinical practice. However, comprehensive cranial imaging is also of tremendous value for timely diagnosis, proper treatment of symptoms and for further research into CHARGE syndrome. We hope the guideline for neuroradiological evaluation will help clinicians provide efficient and comprehensive care for individuals with CHARGE syndrome.
AssuntosSíndrome CHARGE/diagnóstico , Síndrome CHARGE/terapia , Encéfalo/anormalidades , Síndrome CHARGE/genética , Gerenciamento Clínico , Humanos , Neuroimagem/métodos , Guias de Prática Clínica como Assunto
Objective: To evaluate the diagnostic yield of microarray analysis in a hospital-based cohort of children with seizures and to identify novel candidate genes and susceptibility loci for epilepsy. Methods: Of all children who presented with their first seizure in the University Medical Center Groningen (January 2000 through May 2013) (n = 1,368), we included 226 (17%) children who underwent microarray analysis before June 2014. All 226 children had a definite diagnosis of epilepsy. All their copy number variants (CNVs) on chromosomes 1-22 and X that contain protein-coding genes and have a prevalence of <1% in healthy controls were evaluated for their pathogenicity. Results: Children selected for microarray analysis more often had developmental problems (82% vs. 25%, p < 0.001), facial dysmorphisms (49% vs. 8%, p < 0.001), or behavioral problems (41% vs. 13%, p < 0.001) than children who were not selected. We found known clinically relevant CNVs for epilepsy in 24 of the 226 children (11%). Seventeen of these 24 children had been diagnosed with symptomatic focal epilepsy not otherwise specified (71%) and five with West syndrome (21%). Of these 24 children, many had developmental problems (100%), behavioral problems (54%) or facial dysmorphisms (46%). We further identified five novel CNVs comprising four potential candidate genes for epilepsy: MYT1L, UNC5D, SCN4B, and NRXN3. Significance: The 11% yield in our hospital-based cohort underscores the importance of microarray analysis in diagnostic evaluation of children with epilepsy.
PURPOSE: Truncating mutations in the maternally imprinted, paternally expressed gene MAGEL2, which is located in the Prader-Willi critical region 15q11-13, have recently been reported to cause Schaaf-Yang syndrome, a Prader-Willi-like disease that manifests as developmental delay/intellectual disability, hypotonia, feeding difficulties, and autism spectrum disorder. The causality of the reported variants in the context of the patients' phenotypes was questioned, as MAGEL2 whole-gene deletions seem to cause little or no clinical phenotype. METHODS: Here we report a total of 18 newly identified individuals with Schaaf-Yang syndrome from 14 families, including 1 family with 3 individuals found to be affected with a truncating variant of MAGEL2, 11 individuals who are clinically affected but were not tested molecularly, and a presymptomatic fetal sibling carrying the pathogenic MAGEL2 variant. RESULTS: All cases harbor truncating mutations of MAGEL2, and nucleotides c.1990-1996 arise as a mutational hotspot, with 10 individuals and 1 fetus harboring a c.1996dupC (p.Q666fs) mutation and 2 fetuses harboring a c.1996delC (p.Q666fs) mutation. The phenotypic spectrum of Schaaf-Yang syndrome ranges from fetal akinesia to neurobehavioral disease and contractures of the small finger joints. CONCLUSION: This study provides strong evidence for the pathogenicity of truncating mutations of the paternal allele of MAGEL2, refines the associated clinical phenotypes, and highlights implications for genetic counseling for affected families.Genet Med 19 1, 45-52.
AssuntosTranstorno do Espectro Autista/genética , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Síndrome de Prader-Willi/genética , Proteínas/genética , Adolescente , Adulto , Transtorno do Espectro Autista/fisiopatologia , Criança , Pré-Escolar , Cromossomos Humanos Par 15 , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Expressão Gênica , Impressão Genômica , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/fisiopatologia , Masculino , Mutação , Fenótipo , Síndrome de Prader-Willi/fisiopatologia
Phelan-McDermid syndrome (PMS) or 22q13.3 deletion syndrome is a rare neurodevelopmental disorder with at least 60 children and 35 adults diagnosed in the Netherlands. Clinical features are moderate to severe intellectual disability and behavioural problems in the autism spectrum. Other researchers had observed a beneficial effect of intranasal insulin on development and behaviour in a pilot study in six children with PMS. To validate this effect, we conducted a randomized, double-blind, placebo-controlled clinical trial using a stepped-wedge design. From March 2013 to June 2015, 25 children aged 1-16 years with a molecularly confirmed 22q13.3 deletion including the SHANK3 gene participated in the clinical trial for a period of 18 months. Starting 6 months before the trial, children were systematically assessed for cognitive, language and motor development and for adaptive, social and emotional behaviour every 6 months. The second, third and fourth assessments were followed by daily nose sprays containing either intranasal insulin or intranasal placebo for a 6-month period. A fifth assessment was done directly after the end of the trial. Intranasal insulin did not cause serious adverse events. It increased the level of developmental functioning by 0.4-1.4 months per 6-month period, but the effect was not statistically significant in this small group. We found a stronger effect of intranasal insulin, being significant for cognition and social skills, for children older than 3 years, who usually show a decrease of developmental growth. However, clinical trials in larger study populations are required to prove the therapeutic effect of intranasal insulin in PMS.
AssuntosTranstornos Cromossômicos/reabilitação , Insulina/uso terapêutico , Habilidades Sociais , Administração Intranasal , Adolescente , Criança , Desenvolvimento Infantil , Pré-Escolar , Deleção Cromossômica , Transtornos Cromossômicos/tratamento farmacológico , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 22/genética , Método Duplo-Cego , Feminino , Humanos , Lactente , Insulina/administração & dosagem , Insulina/efeitos adversos , Masculino , Proteínas do Tecido Nervoso/genética
Numerous genes are associated with neurodevelopmental disorders such as intellectual disability and autism spectrum disorder (ASD), but their dysfunction is often poorly characterized. Here we identified dominant mutations in the gene encoding the transcriptional repressor and MeCP2 interactor switch-insensitive 3 family member A (SIN3A; chromosome 15q24.2) in individuals who, in addition to mild intellectual disability and ASD, share striking features, including facial dysmorphisms, microcephaly and short stature. This phenotype is highly related to that of individuals with atypical 15q24 microdeletions, linking SIN3A to this microdeletion syndrome. Brain magnetic resonance imaging showed subtle abnormalities, including corpus callosum hypoplasia and ventriculomegaly. Intriguingly, in vivo functional knockdown of Sin3a led to reduced cortical neurogenesis, altered neuronal identity and aberrant corticocortical projections in the developing mouse brain. Together, our data establish that haploinsufficiency of SIN3A is associated with mild syndromic intellectual disability and that SIN3A can be considered to be a key transcriptional regulator of cortical brain development.
AssuntosCórtex Cerebral/patologia , Haploinsuficiência/genética , Deficiência Intelectual/patologia , Proteína 2 de Ligação a Metil-CpG/metabolismo , Mutação/genética , Neurogênese/fisiologia , Proteínas Repressoras/genética , Anormalidades Múltiplas , Adolescente , Adulto , Agenesia do Corpo Caloso/genética , Agenesia do Corpo Caloso/patologia , Animais , Córtex Cerebral/metabolismo , Criança , Pré-Escolar , Deleção Cromossômica , Feminino , Humanos , Deficiência Intelectual/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Fenótipo , Proteínas Repressoras/metabolismo , Síndrome , Adulto Jovem
Mutations in CREBBP cause Rubinstein-Taybi syndrome. By using exome sequencing, and by using Sanger in one patient, CREBBP mutations were detected in 11 patients who did not, or only in a very limited manner, resemble Rubinstein-Taybi syndrome. The combined facial signs typical for Rubinstein-Taybi syndrome were absent, none had broad thumbs, and three had only somewhat broad halluces. All had apparent developmental delay (being the reason for molecular analysis); five had short stature and seven had microcephaly. The facial characteristics were variable; main characteristics were short palpebral fissures, telecanthi, depressed nasal ridge, short nose, anteverted nares, short columella, and long philtrum. Six patients had autistic behavior, and two had self-injurious behavior. Other symptoms were recurrent upper airway infections (n = 5), feeding problems (n = 7) and impaired hearing (n = 7). Major malformations occurred infrequently. All patients had a de novo missense mutation in the last part of exon 30 or beginning of exon 31 of CREBBP, between base pairs 5,128 and 5,614 (codons 1,710 and 1,872). No missense or truncating mutations in this region have been described to be associated with the classical Rubinstein-Taybi syndrome phenotype. No functional studies have (yet) been performed, but we hypothesize that the mutations disturb protein-protein interactions by altering zinc finger function. We conclude that patients with missense mutations in this specific CREBBP region show a phenotype that differs substantially from that in patients with Rubinstein-Taybi syndrome, and may prove to constitute one (or more) separate entities. © 2016 Wiley Periodicals, Inc.
AssuntosProteína de Ligação a CREB/genética , Estudos de Associação Genética , Mutação , Fenótipo , Síndrome de Rubinstein-Taybi/diagnóstico , Síndrome de Rubinstein-Taybi/genética , Adolescente , Adulto , Alelos , Sequência de Aminoácidos , Criança , Pré-Escolar , Exoma , Éxons , Facies , Feminino , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Mutação de Sentido Incorreto , Adulto Jovem
OBJECTIVE: To evaluate whether central adrenal insufficiency (CAI) is present in CHARGE (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth and/or development, Genital hypoplasia, and Ear abnormalities, including deafness) syndrome, a complex malformation disorder that includes central endocrine dysfunction. STUDY DESIGN: Two cross-sectional studies were performed in Dutch (September 2013-February 2015) and Australian (January 2012-January 2014) CHARGE syndrome clinics. Twenty-seven Dutch and 19 Australian patients (aged 16 months-18 years) with genetically confirmed CHARGE syndrome were included. The low-dose adrenocorticotropin (ACTH) test was used to assess CAI in the Dutch cohort. A peak cortisol response less than 18.1 µg/dL (500 nmol/L) was suspected for CAI, and a glucagon stimulation test was performed for confirmation. Australian patients were screened by single measurements of ACTH and cortisol levels. If adrenal dysfunction was suspected, a standard-dose ACTH test was performed. RESULTS: The low-dose ACTH test was performed in 23 patients (median age 8.4 [1.9-16.9] years). Seven patients showed an insufficient maximum cortisol level (10.3-17.6 µg/dL, 285-485 nmol/L), but CAI was confirmed by glucagon stimulation test in only 1 patient (maximum cortisol level 15.0 µg/dL, 415 nmol/L). In the Australian cohort, 15 patients (median age 9.1 [1.3-17.8] years) were screened, and none had CAI. CONCLUSIONS: CAI was not common in our cohorts, and routine testing of adrenal function in children with CHARGE syndrome is not indicated.
AssuntosInsuficiência Adrenal/etiologia , Síndrome CHARGE/complicações , Adolescente , Insuficiência Adrenal/epidemiologia , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Lactente , Masculino
BACKGROUND: Phelan-McDermid syndrome (PMS) or 22q13.3 deletion syndrome is characterized by global developmental delay, cognitive deficits, and behaviour in the autism spectrum. Knowledge about developmental and behavioural characteristics of this rare chromosomal disorder is still limited despite a rapid growing number of diagnoses. Our aim was to study a new and relatively large cohort to further characterize the developmental phenotype of children with PMS. METHODS: We performed a descriptive study of children with a 22q13.3 deletion including SHANK3, aged 8 to 178 months, who were systematically (n = 34) and longitudinally (n = 29) assessed with standardized instruments: Bayley Scales of Infant and Toddler Development, third edition; Wechsler Preschool and Primary Scale of Intelligence, third edition; and Vineland Screener for Social and Adaptive Behavior. RESULTS: Maximal developmental functioning ranged from 34 to 52 months depending on the developmental domain. In general, children performed poorest in the domain of language and best on the domain of motor (young children) or cognitive development (older children). At the individual level, 25 % scored better for receptive and 18 % for expressive language, whereas 22 % scored better for fine and 33 % for gross motor function. Developmental quotients were higher in younger children and decreased with age for all developmental domains, with 38 % of the children showing no improvement of cognitive developmental functioning. Almost all children (33/34) had significant deficits in adaptive behaviour. Children with very small deletions, covering only the SHANK3, ACR, and RABL2B genes, had a more favourable developmental phenotype. CONCLUSIONS: Cognitive, motor, and especially language development were significantly impaired in all children with PMS but also highly variable and unpredictable. In addition, deficits in adaptive behaviour further hampered their cognitive development. Therefore, cognitive and behavioural characteristics should be evaluated and followed in each child with PMS to adapt supportive and therapeutic strategies to individual needs. Further research evaluating the relationship between deletion characteristics and the developmental phenotype is warranted to improve counselling of parents.
CHARGE syndrome is a dominant disorder characterized by ocular colobomata, heart defects, choanal atresia, retardation of growth and development, genital hypoplasia, and ear abnormalities including deafness and vestibular disorders. The majority of individuals with CHARGE have pathogenic variants in the gene encoding CHD7, a chromatin remodeling protein. Here, we present a 15-year-old girl with clinical features of CHARGE syndrome and a de novo 6.5 Mb gain of genomic material at 2p25.3-p25.2. The duplicated region contained 24 genes, including the early and broadly expressed transcription factor gene SOX11. Analysis of 28 other patients with CHARGE showed no SOX11 copy number changes or pathogenic sequence variants. To our knowledge, this child's chromosomal abnormality is unique and represents the first co-occurrence of duplication 2p25 and clinical features of CHARGE syndrome. We compare our patient's phenotype to ten previously published patients with isolated terminal duplication 2p, and elaborate on the clinical diagnosis of CHARGE in the context of atypical genetic findings.
AssuntosAnormalidades Múltiplas/genética , Síndrome CHARGE/genética , Fatores de Transcrição SOXC/genética , Trissomia/genética , Anormalidades Múltiplas/fisiopatologia , Síndrome CHARGE/fisiopatologia , Criança , Cromossomos Humanos Par 2/genética , Variações do Número de Cópias de DNA/genética , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Feminino , Duplicação Gênica/genética , Testes Genéticos , Humanos , Mutação , Fatores de Transcrição SOXC/biossíntese , Trissomia/fisiopatologia
Mutations in more than a hundred genes have been reported to cause X-linked recessive intellectual disability (ID) mainly in males. In contrast, the number of identified X-linked genes in which de novo mutations specifically cause ID in females is limited. Here, we report 17 females with de novo loss-of-function mutations in USP9X, encoding a highly conserved deubiquitinating enzyme. The females in our study have a specific phenotype that includes ID/developmental delay (DD), characteristic facial features, short stature, and distinct congenital malformations comprising choanal atresia, anal abnormalities, post-axial polydactyly, heart defects, hypomastia, cleft palate/bifid uvula, progressive scoliosis, and structural brain abnormalities. Four females from our cohort were identified by targeted genetic testing because their phenotype was suggestive for USP9X mutations. In several females, pigment changes along Blaschko lines and body asymmetry were observed, which is probably related to differential (escape from) X-inactivation between tissues. Expression studies on both mRNA and protein level in affected-female-derived fibroblasts showed significant reduction of USP9X level, confirming the loss-of-function effect of the identified mutations. Given that some features of affected females are also reported in known ciliopathy syndromes, we examined the role of USP9X in the primary cilium and found that endogenous USP9X localizes along the length of the ciliary axoneme, indicating that its loss of function could indeed disrupt cilium-regulated processes. Absence of dysregulated ciliary parameters in affected female-derived fibroblasts, however, points toward spatiotemporal specificity of ciliary USP9X (dys-)function.
AssuntosDeficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Mutação , Ubiquitina Tiolesterase/genética , Adolescente , Sequência de Bases , Criança , Pré-Escolar , Atresia das Cóanas/diagnóstico , Atresia das Cóanas/genética , Deficiências do Desenvolvimento/diagnóstico , Feminino , Genes Ligados ao Cromossomo X , Testes Genéticos , Humanos , Deficiência Intelectual/diagnóstico , Dados de Sequência Molecular , Fenótipo , Ubiquitina Tiolesterase/metabolismo , Inativação do Cromossomo X , Adulto Jovem
BACKGROUND: Clinical and genetic heterogeneity in monogenetic disorders represents a major diagnostic challenge. Although the presence of particular clinical features may aid in identifying a specific cause in some cases, the majority of patients remain undiagnosed. Here, we investigated the utility of whole-exome sequencing as a diagnostic approach for establishing a molecular diagnosis in a highly heterogeneous group of patients with varied intellectual disability and microcephaly. METHODS: Whole-exome sequencing was performed in 38 patients, including three sib-pairs, in addition to or in parallel with genetic analyses that were performed during the diagnostic work-up of the study participants. RESULTS: In ten out of these 35 families (29 %), we found mutations in genes already known to be related to a disorder in which microcephaly is a main feature. Two unrelated patients had mutations in the ASPM gene. In seven other patients we found mutations in RAB3GAP1, RNASEH2B, KIF11, ERCC8, CASK, DYRK1A and BRCA2. In one of the sib-pairs, mutations were found in the RTTN gene. Mutations were present in seven out of our ten families with an established etiological diagnosis with recessive inheritance. CONCLUSIONS: We demonstrate that whole-exome sequencing is a powerful tool for the diagnostic evaluation of patients with highly heterogeneous neurodevelopmental disorders such as intellectual disability with microcephaly. Our results confirm that autosomal recessive disorders are highly prevalent among patients with microcephaly.
AssuntosExoma/genética , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Microcefalia/complicações , Microcefalia/genética , Análise de Sequência de DNA/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto Jovem
We describe an 18-year-old male patient with myoclonic astatic epilepsy (MAE), moderate to severe intellectual disability, behavioural problems, several dysmorphisms and a 1.2-Mb de novo deletion on chromosome 16p11.2. This deletion results in haploinsufficiency of STX1B and other genes. Recently, variants in the STX1B gene have been associated with a wide spectrum of fever-related epilepsies ranging from single febrile seizures to severe epileptic encephalopathies. Two previously reported patients with a STX1B missense variant or deletion were diagnosed with MAE. Our observation of a STX1B deletion in a third patient with MAE therefore supports that STX1B gene variants or deletions can be involved in the aetiology of MAE. Furthermore, STX1B encodes for syntaxin-1B, of which interaction with the protein encoded by the STXBP1 gene is essential for the regulation of the synaptic transmission of neurotransmitters. STXBP1 gene variants have been identified in patients with many different types of epilepsy, including Dravet syndrome and epileptic encephalopathies, suggesting STX1B plays a similar role. We recommend that analysis of STX1B should be considered in the diagnostic work-up of individuals with MAE.


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We are quite pleased this season to have an extra pair of hands. Helene whom all of you will meet over the season is an ex-teacher and has lived in Kenya for over 7 years. Her old school has traveled with us and after Helene ran one school trip, she had the Camp Kenya bug. And so the diary of a…begins… Blogging?… me?!… I canÛªt put my finger on it, but there is something about this blogging idea that doesnÛªt quite compute with meÛ_ But what better way to find out if I would like itÛ_ than trying it!? At least, after one week at Camp Kenya, I already know for sure that each day will offer plenty of magical moments and pictures to share! So here is my first entry! Tuesday 12th July Visit to Ocean Camp ÛÒ Watch the space between the Blue and the White for the Flip-Flop workshop coming very soon! Visit to Kaya Kinondo ÛÒ OoopsÛ_ forgot to take any photos, as we were busy discussing about our project of building a banda for the WomenÛªs Community Group. I promise some photos in a few daysÛ_ Visit to Camp Muhaka ÛÒ First day of action for the Team from Cardinal Heenana, Trafalgar and Ballard schools. Their Community Project at Muhaka for the next 3 days is to build toilets at one of the primary schools. Half a dayÛªs work and already shoulders deepÛ_ Everyone is busyÛ_ quietlyÛ_ as students from the primary school are in class studying five meters away on the right. The Kenyan school calendar runs from January to November, with a short break in August. The teamÛªs other project, one kilometer away, is to build an extension house for the elderly lady of a local family. The sun is hitting now but the wind is strong and the rains come and go quickly at this time of the year. An extra roof and space will certainly make a whole difference to the family. With the guidance of Camp Kenya staff, students are learning quickly the art of building a house with local materials: wood from old coconut trees and sisal poles and plenty of mud to come! Building a house? LetÛªs just do itÛ_ You would have worked out from this first entry that IÛªm a very lucky person this season: I will be moving from one camp to another, working with the students, the teachers, the expedition leaders, the camp managers and the Camp Kenya office in Diani. As teacher liaison, I will be helping to ensure that the amazing projects which are about to take place over the next five weeks on the Kenyan Coast and in Tsavo run effectively in order for the people to be smiling on the photos! I hope I will like bloggingÛ_ and will try to continue sharing our Kenyan moments of the day. As colleagues at the Camp Kenya office keep saying with excitement: ÛÏThe Season has begun!Û HÌ©l̬ne
Reported by on 23rd February 2016