Landscape of Constitutional Variation in Human Disorders

SOX proteins are transcription factors which play a role in regulating the development of progenitor cells and tissue differentiation. Twenty members are known, clustered in eight groups named A through H and sharing a common DNA-binding domain called the HMG (high-mobility-group) box. Eleven of the SOX genes have been associated with genetic disorders so far, covering a broad spectrum of developmental diseases. is a single-exon gene and belongs to the SOXC group, together with and . variants have been recently described to cause a highly penetrant but heterogeneous disorder, with a phenotypic spectrum ranging from mild developmental delays and learning difficulties to intellectual disabilities with congenital anomalies. Nineteen pathogenic variants have been reported to date, generally de novo, heterozygous, and inactivating, either stop-gain or missense, the latter ones primarily targeting the HMG domain. Further, a bi-allelic variant was reported in a single consanguineous family. Copy number variants leading to whole gene deletion or duplication are rare and not clearly associated with any neurodevelopmental disorder. Many open questions remain regarding the definition of variants of unknown significance, a possible role of missense variants outside the HMG domain, genotype-phenotype correlation, the range of phenotypic spectrum and modifying factors, and treatment options.