Non‐coding variation in disorders of sex development

Abstract

Genetic studies in Disorders of Sex Development (DSD), representing a wide spectrum of developmental or functional conditions of the gonad, have mainly been oriented towards the coding genome. Application of genomic technologies, such as whole‐exome sequencing, result in a molecular genetic diagnosis in ∼50% of cases with DSD. Many of the genes mutated in DSD encode transcription factors such as SRY, SOX9, NR5A1, and FOXL2, characterized by a strictly regulated spatiotemporal expression. Hence, it can be hypothesized that at least part of the missing genetic variation in DSD can be explained by non‐coding mutations in regulatory elements that alter gene expression, either by reduced, mis‐ or overexpression of their target genes. In addition, structural variations such as translocations, deletions, duplications or inversions can affect the normal chromatin conformation by different mechanisms. Here, we review non‐coding defects in human DSD phenotypes and in animal models. The wide variety of non‐coding defects found in DSD emphasizes that the regulatory landscape of known and to be discovered DSD genes has to be taken into consideration when investigating the molecular pathogenesis of DSD.

XX Disorder of Sex Development is associated with an insertion on chromosome 9 and downregulation of RSPO1 in dogs (Canis lupus familiaris)

“…XX DSD patients with CNVs near SOX9 are also relevant for comparison, and such syndromic and nonsyndromic patients were recently reviewed [ 75 ]. To summarize, the CNV identified are presumed to alter testis-specific regulatory regions of SOX9 to cause XX DSD.…”

Caring for individuals with a difference of sex development (DSD): a Consensus Statement

“…Cardiovascular pathology in men and women with 45,X/46,XY DSD is similar to that in women with Turner syndrome, irrespective of the clinical phenotype 95 . Coding and structural variations in SOX9 or some of its regulatory regions can cause, apart from XX or XY DSD, a severe skeletal condition known as campomelic dysplasia 32 . Skeletal, as well as renal, involvement is common in MRKH syndrome 96 .…”

Disturbed Ovarian Differentiation in XX;SRY-Negative Dogs

“…NR5A1 [or SF1, Steroidogenic Factor-1), which along with WT1 (Wilms tumor 1) plays a crucial role in the formation of the bipotential gonad, also acts as a SRY-mediated SOX9 enhancer through testis differentiation [35,47]. In some species, like in mice, humans, and dogs, a testisspecific enhancer motif (termed Tesco, RevSex and CanRevSex, respectively) has been demonstrated to mediate SRY and Nr5a1 synergic interaction [48] to enhance the transactivation of SOX9 by multiple folds [41]. Additional contributions of other genes from the SOX family [e.g., SOX3 and SOX10) has also been evidenced [41,49] from the study of DSD conditions.…”