6p25 interstitial deletion in two dizygotic twins with gyral pattern anomaly and speech and language disorder

Submicroscopic 6p25 deletion is now recognized as a clinically identifiable syndrome, characterized by intellectual disability, language impairment, hearing deficit, craniofacial, ophthalmologic, cardiac, and varying central nervous system anomalies. We report on two dyzogotic twins with a maternal segregating hemizygous interstitial deletion on chromosome 6p25.1, spanning 0.9 kb; the smallest ever reported. Both had dysmorphic features (prominence of the metopic suture, synophrys, hypertelorism, down-slanting palpebral fissures, tented mouth), and a distinct brain MRI, showing a focal significant increase of the right peri-frontal subarachnoid space, with shallow sulci and a mild anomaly of the gyral pattern. Such brain anomaly has never been reported in association with del 6p25. Both propositi had a borderline-mild intellectual disability, speech and language difficulties, and behavior abnormalities. Their mother, formally tested, had a borderline cognitive impairment. Although none of the genes mapping to the deleted region are apparently related to the phenotype, LYRM4 resulted down-regulated in the cerebellar cortex of schizophrenia patients compared with controls, and Lyrm4 was down-regulated in the prefrontal cortex of mice with microdeletions in the locus syntenic to human 22q11.2 patients affected by schizophrenia. These data are in agreement with the emerging concept that similar CNVs are pathogenic in patients affected by distinct neurological diseases, and that these loci are more general risk factors for different disorders. The resemblance of our patients to those with the more extensive 6p25.1p25.3 terminal deletion suggests that the gene/s responsible for the physical phenotype should reside in the 6p25.1 genomic region.