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Expanding the phenotype of a recurrent de novo variant in PACS1 causing intellectual disability

To the Editor: Intellectual disabilities (ID), like other neurodevelopmental disorders, are characterized by substantial genetic heterogeneity and clinical variability. Finding the correct genetic diagnosis poses a major challenge even for experienced clinical geneticists. The implementation of genome–wide technologies such as microarray analysis and whole exome sequencing (WES) has dramatically increased the diagnostic yield (1). We applied proband-parents WES in a boy with unexplained ID. The patient is a 3-year-old boy with moderate developmental delay, congenital heart defect, chronic constipation and low levels of immunoglobulins. His medical history and clinical features are detailed in Table 1 and in the Appendix S1, Supporting Information. Previously, conventional chromosomal analysis, microarray analysis and sequence analysis of PTPN11, KRAS, SOS1 and RAF1 had not revealed any disease causing variants. Trio exome analysis revealed a heterozygous de novo missense mutation in exon 4 of PACS1 (c.[607C>T];[=], p.[Arg203Trp];[=], according to NM_018026.3). The variant was confirmed by Sanger sequencing. For detailed information on the methods applied see Appendix S1. The same variant in PACS1 has already been detected in two individuals by Schuurs-Hoeijmakers et al. (2). The authors had adopted proband-parents WES in two individuals with remarkably similar facial dysmorphisms in a cohort of >5000 individuals with ID. Characterization of the two patients lead to the delineation of a novel distinct ID syndrome designated MRD17 (mental retardation autosomal dominant 17, MIM#615009). The two patients reported previously and the one of this report – all males from European descent – share a similar but rather unspecific clinical history (Table 1). They were born with normal birth measurements and their weight and height lies within normal limits, whereas the head circumference is relatively small but still above the third centile. All have moderate ID and a pleasant personality. Organ malformations include urogenital anomalies (2/3), malformation of the cerebellum (1/2), scoliosis (1/3) and heart defects (1/3). One of the patients described in the publication of Schuurs-Hoeijmakers et al. was tested for Cornelia de Lange syndrome, while the combination of feeding difficulties with the facial features and the heart defect prompted us to test our patient for a rasopathy. At the level of the appearance of the three patients, they have strikingly similar and distinctive facial features, which are characterized by the combination of down-slanting palpebral fissures, hypertelorism, a wide mouth with down-turned corners and thin upper lips in the shape of a cupid’s bow (Fig. 1a). Additional overlapping features include large and low-set ears, a bulbous tip of the nose and curly hair. PACS1 is a trans-golgi-membrane traffic regulator that directs protein cargo (3). It is highly expressed in brain during embryonic development and is down regulated in the postnatal period (4). The recurrent variant c.[607C>T];[=], p.[Arg203Trp];[=] is located in close proximity to the CK2-binding motif and therefore possibly influences the binding properties of PACS1 (Fig. 1b). Antisense experiments in zebrafish led to the suggestion that this variant exerts a dominant negative effect by influencing the fate of SOX10-positive neural crest cells, thus creating the facial dysmorphisms (2). However, additional patients and more detailed functional experiments are needed to confirm this hypothesis and establish a genotype–phenotype correlation. Interestingly, despite the application of WES in large cohorts of patients with neurodevelopmental disorders such as ID, autism and epilepsy, neither variants in PACS1 nor in its close family member, PACS2, have been reported in the literature so far. Moreover, microdeletions encompassing PACS1 on 11q13.1 seem to be very rare events. The DECIPHER database lists only one individual carrying a heterozygous deletion of about 1.1 Mb encompassing PACS1 (https://decipher.sanger.ac.uk). The deletion covers additional 45 RefSeq genes, and the patient seems to display a complex pattern of malformations and dysmorphisms characteristic for a contiguous microdeletion syndrome. This individual, therefore, does not add to delineate the phenotype caused by haploinsufficiency of PACS1. In summary, the recurrent variant c.[607C>T];[=], p.[Arg203Trp];[=] in PACS1 causes the ID syndrome MRD17. Here, we report the third patient with MRD17, providing additional evidence that this variant causes a