Biallelic variants in LINGO1 are associated with autosomal recessive intellectual disability, microcephaly, speech and motor delay

Abstract

Purpose: To elucidate the novel molecular cause in two unrelated consanguineous families with autosomal recessive intellectual disability.Methods: A combination of homozygosity mapping and exome sequencing was used to locate the plausible genetic defect in family F162, while only exome sequencing was followed in the family PKMR65. The protein 3D structure was visualized with the University of California-San Francisco Chimera software.Results: All five patients from both families presented with severe intellectual disability, aggressive behavior, and speech and motor delay. Four of the five patients had microcephaly. We identified homozygous missense variants in LINGO1, p.(Arg290His) in family F162 and p.(Tyr288Cys) in family PKMR65. Both variants were predicted to be pathogenic, and segregated with the phenotype in the respective families. Molecular modeling of LINGO1 suggests that both variants interfere with the glycosylation of the protein.Conclusion: LINGO1 is a transmembrane receptor, predominantly found in the central nervous system. Published loss-offunction studies in mouse and zebrafish have established a crucial role of LINGO1 in normal neuronal development and central nervous system myelination by negatively regulating oligodendrocyte differentiation and neuronal survival. Taken together, our results indicate that biallelic LINGO1 missense variants cause autosomal recessive intellectual disability in humans.

Biallelic variants in FBXL3 cause intellectual disability, delayed motor development and short stature

“…The algorithm CATCH (36) that combines the family pedigree information, ROH and exome sequencing data was used to identify and filter the variants segregating with the disease phenotype in each family. All the segregating filtered variants were analyzed as described in our previous studies (19,(59)(60)(61) and were confirmed by Sanger capillary sequencing using oligonucleotide primers designed using Primer3 and BLAST (https://www.ncbi.nlm.nih.gov/tools/ primer-blast/).…”

Bi-allelic Variants in DYNC1I2 Cause Syndromic Microcephaly with Intellectual Disability, Cerebral Malformations, and Dysmorphic Facial Features

“…19 We aligned sequenced reads to the GRCh37 (hg19) 20 reference human genome and performed variant filtering as described. [21][22][23] We conducted genotyping of five nuclear family members (1-IV:7, 1-V:4, 1-VI:1, 1-VI:2, and 1-VI:3) with the Illumina 720K SNP array (HumanOmniExpress Bead Chip by Illumina), and we used PLINK 24 to perform homozygosity mapping. A run of homozygosity (ROH) was defined as a window of 50 consecutive homozygous SNPs; the window allowed a maximum of one mismatch in a homozygous region and was demarcated by the first heterozygous SNP at the edge of each homozygous region.…”

“…25 This program also filters variants on the basis of zygosity, quality score, minor allele frequency, pathogenicity prediction, and conservation scores as described. [21][22][23] All candidate variants were verified further by Sanger sequencing.…”

“…We used our custom analysis paradigm, which employs a minor allele frequency (MAF) threshold of <0.02 in public databases or our in-house, ethnically-matched exomes. The intersection of this dataset with a prioritization algorithm [21][22][23] that merges outputs from in silico prediction tools yielded no pathogenic variants in the known causative genes for microcephaly, intellectual disability, or developmental delay. Next, we overlaid exome data with homozygosity mapping information constructed by genotyping five members of family 1.…”

GPR126: A novel candidate gene implicated in autosomal recessive intellectual disability

“…NGS has made it possible to recognize new genes associated with ID and over 700 genes have been identified to be implicated in this disorder. So far, fewer than 600 of these genes have been associated with autosomal recessive intellectual disability (ARID), which shows the importance of ARID gene identification, especially in populations with frequent parental consanguinity (Ansar et al, ; Najmabadi et al, ).…”