11q13.3q13.4 deletion plus 9q21.13q21.33 duplication in an affected girl arising from a familial four‐way balanced chromosomal translocation

Abstract Background We describe a 13‐year‐old girl with a 11q13.3q13.4 deletion encompassing the SHANK2 gene and a 9q21.13q21.33 duplication. She presented with pre‐ and postnatal growth retardation, global developmental delay, severe language delay, cardiac abnormalities, and dysmorphisms. Her maternal family members all had histories of reproductive problems. Methods Maternal family members with histories of reproductive problems were studied using G‐banded karyotyping and optical genome mapping (OGM). Long‐range PCR (LR‐PCR) and Sanger sequencing were used to confirm the precise break point sequences obtained by OGM. Results G‐banded karyotyping characterized the cytogenetic results as 46,XX,der(9)?del(9)(q21q22)t(9;14)(q22;q24),der(11)ins(11;?9)(q13;?q21q22),der(14)t(9;14). Using OGM, we determined that asymptomatic female family members with reproductive problems were carriers of a four‐way balanced chromosome translocation. Their karyotype results were further refined as 46,XX,der(9)del(9)(q21.13q21.33)t(9;14)(q21.33;q22.31),der(11)del(11)(q13.3q13.4)ins(11;9)(q13.3;q21.33q21.13),der(14)t(9:14)ins(14;11)(q23.1;q13.4q13.3). Thus, we confirmed that the affected girl inherited the maternally derived chromosome 11. Furthermore, using LR‐PCR, we showed that three disease‐related genes (TMC1, NTRK2, and KIAA0586) were disrupted by the breakpoints. Conclusions Our case highlights the importance of timely parental origin testing for patients with rare copy number variations, as well as the accurate characterization of balanced chromosomal rearrangements in families with reproductive problems. In addition, our case demonstrates that OGM is a useful clinical application for analyzing complex structural variations within the human genome