We studied two unrelated boys with intellectual disability (ID) and a striking facial resemblance suggestive of a hitherto unappreciated syndrome. Exome sequencing in both families identified identical de novo mutations in PACS1, suggestive of causality. To support these genetic findings and to understand the pathomechanism of the mutation, we studied the protein in vitro and in vivo. Altered PACS1 forms cytoplasmic aggregates in vitro with concomitant increased protein stability and shows impaired binding to an isoform-specific variant of TRPV4, but not the full-length protein. Furthermore, consistent with the human pathology, expression of mutant PACS1 mRNA in zebrafish embryos induces craniofacial defects most likely in a dominant-negative fashion. This phenotype is driven by aberrant specification and migration of SOX10-positive cranial, but not enteric, neural-crest cells. Our findings suggest that PACS1 is necessary for the formation of craniofacial structures and that perturbation of its functions results in a specific syndromic ID phenotype.
Variants in CLCN4, which encodes the chloride/hydrogen ion exchanger CIC-4 prominently expressed in brain, were recently described to cause X-linked intellectual disability and epilepsy. We present detailed phenotypic information on 52 individuals from 16 families with CLCN4-related disorder: 5 affected females and 2 affected males with a de novo variant in CLCN4 (6 individuals previously unreported) and 27 affected males, 3 affected females and 15 asymptomatic female carriers from 9 families with inherited CLCN4 variants (4 families previously unreported). Intellectual disability ranged from borderline to profound. Behavioral and psychiatric disorders were common in both child- and adulthood, and included autistic features, mood disorders, obsessive–compulsive behaviors and hetero- and autoaggression. Epilepsy was common, with severity ranging from epileptic encephalopathy to well-controlled seizures. Several affected individuals showed white matter changes on cerebral neuroimaging and progressive neurological symptoms, including movement disorders and spasticity. Heterozygous females can be as severely affected as males. The variability of symptoms in females is not correlated with the X inactivation pattern studied in their blood. The mutation spectrum includes frameshift, missense and splice site variants and one single-exon deletion. All missense variants were predicted to affect CLCN4’s function based on in silico tools and either segregated with the phenotype in the family or were de novo. Pathogenicity of all previously unreported missense variants was further supported by electrophysiological studies in Xenopus laevis oocytes. We compare CLCN4-related disorder with conditions related to dysfunction of other members of the CLC family.
Intellectual disability (ID) is a heterogeneous disorder with an unknown molecular etiology in many cases. Previously, X-linked ID (XLID) studies focused on males due to the hemizygous state of their X chromosome. Carrier females are generally unaffected due to the presence of a second normal allele, or inactivation of the mutant X chromosome in most of their cells (skewing). However, in female ID patients, we hypothesized that the presence of skewing of X-inactivation would be an indicator for an X chromosomal ID cause. We analysed the X-inactivation patterns of 288 females with ID, and found that 22 (7.6%) had extreme skewing (>90%), which is significantly higher than observed in the general population (3.6%; p=0.029). Whole exome sequencing of 19 females with extreme skewing revealed causal variants in 6 females in the XLID genes DDX3X, NHS, WDR45, MECP2 and SMC1A. Interestingly, variants in genes escaping X-inactivation presumably cause both XLID and skewing of X-inactivation in 3 of these patients. Moreover, variants likely accounting for skewing only, were detected in MED12, HDAC8 and TAF9B. All tested candidate causative variants were de novo events. Hence, extreme skewing is a good indicator for the presence of X-linked variants in female patients.
The evaluation of facial dysmorphism is a critical step toward reaching a diagnostic. The aim of the present study was to evaluate the ability to interpret facial morphology in African children with intellectual disability (ID). First, 10 experienced clinicians (five from Africa and five from Europe) rated gestalt in 127 African non-Down Syndrome (non-DS) patients using either the score 2 for 'clearly dysmorphic', 0 for 'clearly non dysmorphic' or 1 for 'uncertain'. The inter-rater agreement was determined using kappa coefficient. There was only fair agreement between African and European raters (kappa-coefficient = 0.29). Second, we applied the FDNA Face2Gene solution to assess Down Syndrome (DS) faces. Initially, Face2Gene showed a better recognition rate for DS in Caucasian (80%) compared to African (36.8%). We trained the Face2Gene with a set of African DS and non-DS photographs. Interestingly, the recognition in African increased to 94.7%. Thus, training improved the sensitivity of Face2Gene. Our data suggest that human based evaluation is influenced by ethnic background of the evaluator. In addition, computer based evaluation indicates that the ethnic of the patient also influences the evaluation and that training may increase the detection specificity for a particular ethnic.
We report the clinical findings in 5 patients with a terminal deletion of the short arm of chromosome 8. Mild developmental delay was constantly present, in association with microcephaly in 4 of 5 patients. Facial anomalies were mild or absent. A congenital heart defect was present in 3 patients: an atrioventricular septal defect (AVSD) in 2 and an atrial septal defect type II (ASDII) with pulmonary stenosis in one. A highly similar pattern of behavioural difficulties was present in the 3 older children (8-11 years), with outbursts of aggressiveness and destructive behaviour. Follow-up in one patient showed that at the age of 16 years, these behavioural problems had largely disappeared. This observation suggests that in addition to mental retardation, microcephaly, congenital heart defect (typically AVSD), a terminal deletion of chromosome 8p may be associated with a characteristic behavioural phenotype during childhood.
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