A Case of Agonadism, Skeletal Malformations, Bicuspid Aortic Valve, and Delayed Development with a 16p13.3 Duplication Including GNG13 and SOX8 Upstream Enhancers: Are Either, Both or Neither Involved in the Phenotype?

We report a female patient with delayed growth and development, skeletal and cardiac defects, and a male XY sex chromosome complement with early failure of gonad development. SRY sequencing was normal. Array comparative genome hybridization (CGH) analysis revealed a gain in copy number in the subtelomeric region of the short arm of chromosome 16, encompassing a region of approximately 560 kb in size including GNG13 which may be involved in ovarian development. The proximal breakpoint of the duplication maps about 18 kb upstream of SOX8 and involves evolutionary conserved regulatory elements. SOX8, like SOX9, is a transcription factor expressed in many tissues, including neural crest, nervous system, muscle, cartilage, adrenal gland, kidney, and testis. There was no increase in GNG13 or SOX8 expression in the patient's lymphoblastoid line. It is possible that an alteration of SOX8 or/and GNG13 expression is responsible for the multiple congenital anomalies and sex reversal in our patient.