Novel candidate genes and variants underlying autosomal recessive neurodevelopmental disorders with intellectual disability

Human Genetics
Regie Lyn P Santos-CortezSuzanne M Leal

Abstract

Identification of Mendelian genes for neurodevelopmental disorders using exome sequencing to study autosomal recessive (AR) consanguineous pedigrees has been highly successful. To identify causal variants for syndromic and non-syndromic intellectual disability (ID), exome sequencing was performed using DNA samples from 22 consanguineous Pakistani families with ARID, of which 21 have additional phenotypes including microcephaly. To aid in variant identification, homozygosity mapping and linkage analysis were performed. DNA samples from affected family member(s) from every pedigree underwent exome sequencing. Identified rare damaging exome variants were tested for co-segregation with ID using Sanger sequencing. For seven ARID families, variants were identified in genes not previously associated with ID, including: EI24, FXR1 and TET3 for which knockout mouse models have brain defects; and CACNG7 and TRAPPC10 where cell studies suggest roles in important neural pathways. For two families, the novel ARID genes CARNMT1 and GARNL3 lie within previously reported ID microdeletion regions. We also observed homozygous variants in two ID candidate genes, GRAMD1B and TBRG1, for which each has been previously reported in a single family. An...Continue Reading

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Citations

Aug 4, 2020·American Journal of Medical Genetics. Part a·Marianna FarnèPaolo Prontera
Jul 10, 2020·Journal of Neurochemistry·Debra AbramovJacqueline Burré
Sep 29, 2020·Frontiers in Neuroscience·María Teresa Flores-DorantesRuth Gutiérrez-Aguilar
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May 2, 2021·Biochimica Et Biophysica Acta. Molecular and Cell Biology of Lipids·Tomoki Naito, Yasunori Saheki
Aug 29, 2021·BMC Medical Genomics·Memoona RasheedMuhammad Ansar

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Methods Mentioned

BETA
exome sequencing
genotyping
Chip
glycosylation

Software Mentioned

ToppGene
MT MutationTaster
PolyPhen
dbNSFP
gnomAD
MA MutationAssessor
BrainSpan
metaSVM
NetworkAnalyst
fathmm

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