The guidelines provided by American College of Medical Genetics and Genomics (ACMG) and the Association of Molecular Pathology (AMP) (ACMG/AMP guidelines) suggest a framework for the classification of clinical variants. The obtained results suggest that further exploration of PPI networks combining ASD and BAP risk genes can be used to identify novel or overlooked ASD molecular mechanisms. The results also point to several additional biological pathways (circadian entrainment, NCAM and BTN family interactions, and interaction between L1 and Ankyrins) and hub genes (CFTR, NOD2, PPP2R2B, and TTR). Perhaps these pathways are crucial not only for the development of ASD but also for ВАР. Several previously well-described enriched pathways were identified, including ion channel activity, regulation of synaptic function, and membrane depolarization. The variants were analyzed in the context of gene networks and pathways. Here, a total of 650,000 genetic markers were tested in four Kazakhstani multiplex families with ASD and BAP to obtain data on de novo mutations (DNMs), common, and rare inherited variants that may contribute to the genetic risk for developing autistic traits. The study of extended pedigrees containing autism spectrum disorder- (ASD-) related broader autism phenotypes (BAP) offers a promising approach to the search for ASD candidate variants. Deletions covering the NSD1 locus were not found in the patients analyzed here. The results indicate that the great majority of patients with Sotos syndrome are caused by mutations in NSD1. We tested for large deletions by FISH analysis but were not able to identify any deletion cases. In contrast to the high mutation detection rate in Sotos syndrome, none of the patients with Weaver syndrome, unclassified overgrowth/mental retardation and macrocephaly/mental retardation, harbored NSD1 mutations. The best correlation between clinical assessment and molecular results was obtained for the Sotos facial gestalt in conjunction with overgrowth, macrocephaly, and developmental delay. The mutations (six nonsense, eight frame shifts, three splice site, one missense, one in-frame deletion) are expected to result in an impairment of NSD1 function. We were able to identify mutations within the NSD1 gene in 18 patients and the familial case with Sotos syndrome (90%). In order to investigate a possible phenotype-genotype correlation and to further define the predictive value of NSD1 mutations, we performed mutational analysis of the NSD1 gene in 20 patients and one familial case with Sotos syndrome, five patients with Weaver syndrome, six patients with unclassified overgrowth/mental retardation, and six patients with macrocephaly/mental retardation. Recently, deletions encompassing the nuclear receptor binding SET-Domain 1 (NSD1) gene have been described as the major cause of Japanese patients with the Sotos syndrome, whereas point mutations have been identified in the majority of European Sotos syndrome patients.

Psi overgrowth spell