ClinVar Genomic variation as it relates to human health

Individuals with this variant have white matter hyperintensities on brain MRI with associated language delay and/or autism spectrum disorder. In all cases for which parental samples were available, the deletion was inherited from a parent with a history of language delay and/or white matter hyperintensities. (less)

In 15 probands with specific language impairment-5 (SLI5; 615432) characterized by early language delay and T2-weighted white matter hyperintensities on brain imaging, Wiszniewski et al. (2013) identified a heterozygous 4-kb deletion at chromosome 2q36.3 that removed the penultimate exon 3 of the TM4SF20 gene. Sequencing revealed a complex genomic rearrangement consisting of a 2.3-kb deletion with a GT microhomology at the first junction and a 1.7-kb deletion with insertion of a T at the second junction; both deletions were separated by a neutral copy number genomic segment of approximately 100 bp. Expression of a minigene construct harboring the variant into HEK293 cells showed that the variant resulted in the deletion of exon 3 and introduction of a premature stop codon (Met84Ter) in the terminal exon, resulting in a stable truncated message. Transfection of the variant into mouse neuroblastoma cells resulted in mislocalization of the truncated protein to the cytoplasm. The first 12 probands were ascertained from a group of 15,493 children who were referred for wide-ranging indications and underwent oligonucleotide-based whole-genome exon-focused array CGH. However, the variant was found only among the 6,390 patients referred for developmental delay, speech/language impairment, and/or brain imaging abnormalities. The same variant was found in 4 (5%) of 76 Vietnamese children from a second cohort evaluated for communication disorders; only 3 of these families were further studied in detail. In 6 families, the deletion allele fully segregated with early childhood language delay. The deletion allele segregated with white matter abnormalities in some families, but showed incomplete penetrance. Finally, the same deletion was found in 4 (0.050) of 79 Vietnamese children from a third cohort with communication disorders. The deletion was not found in the 1000 Genomes Project database (2/24/2012), which contained no samples from Southeast Asia, but was found in 46 (2.3%) of 2,018 Vietnamese umbilical cord samples, indicating an allele frequency of 1.1% in the Vietnamese Kinh ethnic group. Haplotype analysis suggested a founder effect. Wiszniewski et al. (2013) postulated a toxic effect of the accumulated protein, rather than haploinsufficiency or a dominant-negative effect, because one of the parent carriers was homozygous for the variant and did not have a different phenotype. (less)