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Phenotypic and Genotypic Characterization of Families With Complex Intellectual Disability Identified Pathogenic Genetic Variations in Known and Novel Disease Genes Publisher Pubmed



Darvish H1, 2 ; Azcona LJ3, 4 ; Tafakhori A5 ; Mesias R3, 6 ; Ahmadifard A7 ; Sanchez E3 ; Habibi A5 ; Alehabib E7 ; Johari AH7 ; Emamalizadeh B8 ; Jamali F7 ; Chapi M7 ; Jamshidi J9, 10 ; Kajiwara Y11, 12 Show All Authors
Authors
  1. Darvish H1, 2
  2. Azcona LJ3, 4
  3. Tafakhori A5
  4. Mesias R3, 6
  5. Ahmadifard A7
  6. Sanchez E3
  7. Habibi A5
  8. Alehabib E7
  9. Johari AH7
  10. Emamalizadeh B8
  11. Jamali F7
  12. Chapi M7
  13. Jamshidi J9, 10
  14. Kajiwara Y11, 12
  15. Paisanruiz C4, 12, 13, 14, 15

Source: Scientific Reports Published:2020


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 diseases with a variety of mutated genes and heterogeneous phenotypic manifestations, allowing for the identification of novel mutations, genes, and phenotypes, and leading to improvements in both diagnostic strategies and functional characterization of disease mechanisms. © 2020, The Author(s).
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