Characterization of a chromosome rearrangement associated with cardiopathy and autism

Chromosomal rearrangements have been associated with multiple congenital abnormalities, including malformative syndromes and global developmental delay. The aim of this study was identification of candidate genes for a complex phenotype characterized by cardiopathy and autism, identified in an individual with a chromosome translocation t(4;7)(q21.1;p21.2). Since classical and molecular cytogenetic analyses have low resolutions, large-insert whole-genome sequencing (liWGS) was applied for identification and mapping of structural chromosomal alterations. By this approach, the 4q21.1 breakpoint was identified between genomic positions chr4:73,918,924-74,049,529 on 4q13.3, whereas the 7p21.2 breakpoint between chr7:13,184,731-14,536,001 [GRCh38/hg38]; suggesting the occurrence of deletions at both breakpoints. Additionally, a 473Kb deletion on 2p16.3 was also identified in the proband. Nucleotide-level resolution of the breakpoints and familial segregation analysis were carried out by amplification of the junction fragments and Sanger sequencing. At the 4q13.3 breakpoint, the 130Kb deletion erases four genes PF4, PPBP, CXCL5 and CXCL3, whereas at 7p21.2, the 1351Kb deletion removes the entire ETV1 and disrupts DGKB and the long non-coding intergenic (Linc) RNA AC011288.2. Furthermore, at this breakpoint region, genomic array analysis identified in the proband’s father a 742Kb deletion comprising DGKB and ETV but not the LincRNA AC011288.2. The maternally inherited 473Kb deletion on 2p16.3 removes the first 5 exons of NRXN1, a gene associated with Pitt-Hopkins like syndrome (OMIM #614325), susceptibility to schizophrenia and chromosome 2p16.3 deletion (OMIM #614332). Similar deletions have been reported with incomplete penetrance and variable expressivity. Several genes from the 7p21.2 breakpoint region and especially those affected by the deletion, DGKB, ETV1 and LincRNA AC011288.2, have been linked with cognitive, speech, language and auditory disorders. In conclusion, coinheritance of the maternally derived deletion on 2p16.3 and the deletion at the breakpoint of the der(7) on 7p21.2 appear to be the most contributively alterations for the proband’s phenotype. At the time, NRXN1, DGKB, ETV1 and LincRNA AC011288.2 are the most likely genes to be responsible for the proband’s phenotype, being those mainly characterised by cardiopathy and autism.