WAC (WW Domain Containing Adaptor With Coiled-Coil) mutations have been reported in only 20 individuals presenting a neurodevelopmental disorder characterized by intellectual disability, neonatal hypotonia, behavioral problems, and mildly dysmorphic features. Using targeted deep sequencing, we screened a cohort of 630 individuals with variable degrees of intellectual disability and identified five WAC rare variants: two variants were inherited from healthy parents; two previously reported de novo mutations, c.1661_1664del (p.Ser554*) and c.374C>A (p.Ser125*); and a novel c.381+2T>C variant causing the skipping of exon 4 of the gene, inherited from a reportedly asymptomatic father with somatic mosaicism. A phenotypic evaluation of this individual evidenced areas of cognitive and behavioral deficits. The patient carrying the novel splicing mutation had a clinical history of encephalopathy related to status epilepticus during slow sleep (ESES), recently reported in another WAC individual. This first report of a WAC somatic mosaic remarks the contribution of mosaicism in the etiology of neurodevelopmental and neuropsychiatric disorders. We summarized the clinical data of reported individuals with WAC pathogenic mutations, which together with our findings, allowed for the expansion of the phenotypic spectrum of WAC-related disorders.

Rivista di formazione e di aggiornamento professionale del pediatra e del medico di base, realizzata in collaborazione con l'Associazione Culturale Pediatri

Background: Joubert syndrome (JS) is a multi-systemic ciliopathy, characterized by intellectual disability and congenital anomalies involving the brain, kidney, heart, and eye. Even if clinical presentation is variable, most authors consider a brain abnormality known as the molar tooth sign (MTS) as mandatory for diagnosis. About 40 genes were identified to be associated with JS, usually with an autosomal recessive pattern. KATNIP variants represent a rare cause of JS; only six families were previously reported. Methods: We performed exome sequencing in a child with a syndromic phenotype, described the clinical features and molecular findings, and performed a review of the literature to identify known individuals with pathogenic variants in KATNIP, highlighting clinical characteristics and gene-phenotype correlations. Results: Using exome sequencing, we identified a homozygous novel frameshift variant c.808del, p.Ser270ValfsTer28 in KATNIP in a 5-year-old male from a consanguineous family of Roma ethnic background. Notable clinical features of the proband include severe developmental delay, hypotonia, and post-axial polydactyly. He did not have MTS, but showed severe anemia and esophageal atresia, which was already reported in association with a KATNIP variant. We collected the phenotypes of all reported patients and discussed common and distinct features with respect to typical JS. Affected individuals shared JS clinical features, although the typical MTS was not always present, polydactyly and renal abnormalities were absent, while pituitary abnormalities were common. Conclusions: Our report provides new data for KATNIP-related JS, expanding the clinical phenotypic spectrum and suggesting a possible role of KATNIP defects in the development of esophageal atresia.