Phenotypic and genotypic characterization of families with complex intellectual disability identified pathogenic genetic variations in known and novel disease genes

Abstract

Intellectual disability (ID), which presents itself during childhood, belongs to a group of neurodevelopmental disorders (NDDs) that are clinically widely heterogeneous and highly heritable, often being caused by single gene defects. Indeed, NDDs can be attributed to mutations at over 1000 loci, and all type of mutations, ranging from single nucleotide variations (SNVs) to large, complex copy number variations (CNVs), have been reported in patients with ID and other related NDDs. In this study, we recruited seven different recessive NDD families with comorbidities to perform a detailed clinical characterization and a complete genomic analysis that consisted of a combination of high throughput SNP-based genotyping and whole-genome sequencing (WGS). Different disease-associated loci and pathogenic gene mutations were identified in each family, including known (n = 4) and novel (n = 2) mutations in known genes (NAGLU, SLC5A2, POLR3B, VPS13A, SYN1, SPG11), and the identification of a novel disease gene (n = 1; NSL1). Functional analyses were additionally performed in a gene associated with autism-like symptoms and epileptic seizures for further proof of pathogenicity. Lastly, detailed genotype-phenotype correlations were carried out to assist with the diagnosis of prospective families and to determine genomic variation with clinical relevance. We concluded that the combination of linkage analyses and WGS to search for disease genes still remains a fruitful strategy for complex

Familial SYN1 Pathogenic Mutations Related Neurodevelopmental Disorders in Asian Pediatric Patients

“…Since Garcia CC et al rstly connected SYN1 mutation with neurodevelopmental disorder in 2004, 16 causative variants including ten missense mutations, ve nonsense mutations, and one splicing site mutation in the gene have been identi ed (containing this study) (Fig. 2) [1,2,[7][8][9][10][11][12][13][14][15][16]. These variants are clustered in B linker domain (A51G, S79W), actin-binding and synaptic-vesicle binding C-domain (W126X, W126R, c.527+1G>A, S212I, G240R, V266M, W356X, T359K, R420G) and proline-rich D-domain (R422X, Q482X, A550T, Q555X, T567A) of the encoded protein as indicated (Fig.…”

“…To better understand the clinical characteristics of SYN1-related disorder, we conducted a literature review of all reported pedigrees from the Pubmed and Embase on English articles. Clinical information of 7 pedigrees with the disorder from 7 studies was collected in the report (Table 1) [2,[9][10][11][12][13][14], and other cases were excluded for lack of detail descriptions [1,7,8,15,16]. Overall, we noticed that females are less susceptible than males due to X-chromosome random inactivation (XCI), however, few female carriers presented with mild intellectual disability and febrile seizures [8,14].…”

“…Several functional analyses have been done in recent studies to elucidate the possible mechanisms involved in SYN1-related disorder [1,12,14]. Compared to human SYN1 wildtype, expression of human SYN1 mutants such as S79W, A550T, T567A in synapsin-I (SynI) knockout (KO) mouse neurons failed to rescue aberrant size and tra cking of synaptic vesicle pools and led to defective nerve terminal function [1,14].…”

“…Compared to human SYN1 wildtype, expression of human SYN1 mutants such as S79W, A550T, T567A in synapsin-I (SynI) knockout (KO) mouse neurons failed to rescue aberrant size and tra cking of synaptic vesicle pools and led to defective nerve terminal function [1,14]. R420Q variant expression in human primary hippocampal neurons signi cantly reduced neurite outgrowth and development [12]. These ndings implicate that SYN1 mutations detected in neurodevelopmental disorders lead to loss-of-function of Synapsin-I protein in the brain network, suggesting that patients with the disease might bene t from the augmentation of the protein function.…”

Assessing Lysosomal Disorders in the NGS Era: Identification of Novel Rare Variants

“…Defects in this gene result in MPS III B (MIM# 252920) [35] which is characterized by intralysosomal accumulation and urinary excretion of heparan sulfate. The p.Asp312Asn NAGLU pathogenic variant has already been reported in two independent studies [18,36]. It was first identified in a French patient [18] in heterozygosity with yet another MPS IIIB-causing variant p.Arg565Gln [37].…”