Specific Language Impairment 5

A number sign (#) is used with this entry because susceptibility to specific language impairment-5 (SLI5) is conferred by heterozygous mutation in the TM4SF20 gene (615404) on chromosome 2q36.

Description

Specific language impairment-5 is characterized by a delay in early speech acquisition and is usually associated with cerebral white matter abnormalities on brain MRI. Some individuals may show disorders in communication, consistent with autism spectrum disorder, or global developmental delay, although others ultimately show normal cognitive function. Penetrance is incomplete and expressivity is variable. This type of disorder is observed most commonly among individuals of East Asian descent (summary by Wiszniewski et al., 2013).

For a phenotypic description and a discussion of genetic heterogeneity of specific language impairment, see SLI1 (602081).

Clinical Features

Wiszniewski et al. (2013) reported 15 probands with early language delay associated in most cases with cerebral T2-weighted white matter hyperintensities. All but 1 patient originated from Southeast Asia, mainly from Vietnam; 1 patient was reportedly of Hispanic descent but was adopted. The children were referred for genetic testing due to early childhood communication disorders ranging from early language delay to autism spectrum disorder; none had any significant facial dysmorphism or other congenital anomalies. Ten (71%) of 14 probands who underwent brain imaging showed cerebral T2-weighted white matter hyperintensities, mainly in the periventricular and deep white matter regions, and enlarged vascular spaces. Three of the probands had carrier sibs who were similarly affected, but 2 other probands had sibs without the deletion who had language delay. Eight of 10 carrier parents also had white matter hyperintensities on brain imaging, many of whom had early language delay. Parents with early language delay showed high educational achievement as adults, but neuropsychologic testing of those with white matter lesions suggested mild impairments in visuospatial functioning, verbal learning, and problem solving. The white matter findings were suggestive of remote small vascular insults rather than demyelination.

Molecular Genetics

In 15 probands with early language delay and white matter hyperintensities, Wiszniewski et al. (2013) identified a heterozygous 4-kb deletion at chromosome 2q36.3 that removed the penultimate exon 3 of the TM4SF20 gene (615404.0001). Sequencing revealed a complex genomic rearrangement that resulted in the deletion of exon 3 and introduction of a premature stop codon (met84 to ter) 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 database, which contains 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.