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

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 additional 14 families have homozygous variants in established ID genes, of which 11 variants are novel. All ARID genes have increased expression in specific structures of the developing and adult human brain and 91% of the genes are differentially expressed in utero or during early childhood. The identification of novel ARID candidate genes and variants adds to the knowledge base that is required to further understand human brain function and development.

Delineation of the First Human Mendelian Disorder of the DNA Demethylation Machinery: TET3 Deficiency

“…Five cases in three distinct families had bi-allelic variants, consistent with autosomal recessive inheritance (Table 1; Figure 1). Two of these individuals were compound heterozygotes, whereas the other three were siblings from a consanguineous family homozygous for the same variant (Table 1; Figure 1) 22 . In all three of the autosomal recessive families, at least one parent appeared mildly affected.…”

“…Individuals 3-I, 3-II, and 3-III were consented for research-based exome sequencing as described 22 , and individuals 7-I and 7-II were consented for research-based trio exome sequencing through the Deciphering Developmental Disorders (DDD) study 35 .…”

“…Furthermore, inhibition or depletion of Tet3 in mouse differentiated neurons can impact synaptic function [18][19][20] . In humans, TET3 is highly intolerant to loss-of-function alleles in control databases 21 , and homozygous missense variants in TET3 were recently implicated as a possible cause for autosomal recessive intellectual disability in a single consanguineous family (further described here as family 3) 22 . Together, these findings illustrate the important role of TET3 in early embryonic development and neuronal function.…”

“…Standard bioinformatics analysis revealed bi-allelic (individual 2) and mono-allelic (individual 4) rare variants in TET3, which were subsequently confirmed by Sanger sequencing. Individuals 3-I, 3-II, and 3-III had exome sequencing performed as described22 . Individual 5 had trio exome sequencing performed with standard bioinformatics analysis, which identified a de novo monoallelic variant in TET3; the variant was confirmed with Sanger sequencing.…”

A patient with novel MBOAT7 variant: The cerebellar atrophy is progressive and displays a peculiar neurometabolic profile

“…In 2016, Johansen et al (2016) reported for the first time 16 patients from six different consanguineous families harboring homozygous inactivating variants in the MBOAT7 gene (OMIM 606048). Since then, other 27 patients with MBOAT7 defects were identified (Hu et al, 2019; Jacher, Roy, Ghaziuddin, & Innis, 2019; Khan et al, 2019; Santos‐Cortez et al, 2018; Yalnızoǧlu et al, 2019). As summarized by Khan et al (2019), 13 different MBOAT7 variants in 18 families have been described until now, of which 5 are frameshift mutations, 2 are splice, 1 is nonsense, 3 are missense, 1 is a 21 bp in frame deletion, 1 is a 11,549 bp deletion.…”