Disorders that are inherited in an AR manner manifest only when both copies of a gene pair located on a non-sex chromosome have a mutation (Tables 47-4, 47-5). Affected children usually are born to unaffected parents, each of whom carries one copy of the mutation. If both members of a couple are carriers (or heterozygotes) for this mutation, each of their offspring has a 25% chance of being affected (Fig. 47-3).
SEE CHAPTER 150.
MFS† (Z ≥2, if >20 years) (Z ≥3, if <20 years)
Facial features (3 of 5)§ 1
Data from Loeys BL, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet 47:476-485, 2010. FBN1, Fibrillin-1; MASS, myopia, mitral valve prolapse, borderline aortic root dilatation (Z <2), striae, skeletal findings; MVPS, mitral valve prolapse syndrome. *Aortic root dilatation (measured at the Sinuses of Valsalva); †Loeys-Dietz syndrome (LDS), Shprintzen-Goldberg syndrome (SGS), and the vascular form of Ehlers Danlos (vEDS) should be excluded. If clinical features are suggestive, then DNA testing for TGFBR1, TGFBR2 (LDS), COL3A1 (vEDS) or collagen biochemistry should be done to help rule out these disorders.
‡Maximum Total: 20 points; more than 7 points indicates systemic involvement. §Facial Features: Dolicocephaly, enophthalmos, downslanting palpebral fissures, malar hypoplasia, retrognathia.
SEE CHAPTERS 55 AND 185.
More than 1000 genes have been identified on the X chromosome, whereas only about 200 are believed to be present on theY chromosome. Females, whose cells have two copies of an X chromosome, possess two copies of each gene on the X chromosome, whereas males, who have one X chromosome and a Y chromosome, have only one copy of these genes. Early in femaleembryonic development, one X chromosome is randomly inactivated in each cell. There are many X-linked disorders (colorblindness, Duchenne muscular dystrophy, hemophilia A) in which heterozygous (carrier) females show some manifestationsof the disorder due to skewed X chromosome inactivation.
Adrenal hyperplasia, congenital 1:5000 Phenotype variation corresponds roughly to allelic variation. A deficiency causes (CAH, 21-hydroxylase deficiency, virilization in females. CA21H, CYP21, cytochrome
The gene is located at 6p21.3 within the HLA complex and within 0.005 centimorgans P450, subfamily XXI) (cM) of HLA B
Cystic fibrosis (CF) 1:2500 whites The gene CF transmembrane conductance regulator (CFTR) is on chromosome 7q31.2
Friedreich ataxia (FA, frataxin) 1:25,000 Frataxin is a mitochondrial protein involved with iron metabolism and respiration. The gene is on chromosome 9q13-q21, and the common mutation is a GAA expanded triplet repeat located in the first intron of the gene. FA does not show anticipation
Trait appears in siblings, not in their parents or their offspring
On average, 25% of siblings of the proband are affected (at the time of conception, each sibling has a 25% chance of being affected)
A normal sibling of an affected individual has a two thirds chance of being a carrier (heterozygote)
Males and females are likely to be affected equally
Rare traits are likely to be associated with parental consanguinity