SIN3A Defects Associated with Syndromic Congenital Hypogonadotropic Hypogonadism: An Overlap with Witteveen-Kolk Syndrome

Abstract

Introduction: Congenital hypogonadotropic hypogonadism (CHH) is a rare condition caused by GnRH deficiency. More than 40 genes have been associated with the pathogenesis of CHH, but most cases still remain without a molecular diagnosis. Mutations involving the same gene (e.g. FGFR1, PROK2/PROKR2, CHD7) were found to cause normosmic CHH and Kallmann syndrome, with and without associated phenotypes, illustrating the coexistence of CHH with signs of other complex syndromes. The Witteveen-Kolk syndrome (WITKOS), caused by defects of the SIN3A gene, is a heterogeneous disorder characterized by distinctive facial features, microcephaly, short stature, delayed cognitive and motor development. Although micropenis and cryptorchidism have been reported in this syndrome, WITKOS has not been formally associated with CHH so far. Patients and Methods: A man with Kallmann syndrome (KS) associated with mild syndromic features (S1) and a boy with global developmental delay, syndromic short stature, micropenis and cryptorchidism (S2), in whom common genetic defects associated with CHH and short stature had been previously excluded, were studied by either chromosomal microarray analysis (CMA) or whole exome sequencing (WES). Results: Rare SIN3A pathogenic variants were identified in these two unrelated patients with CHH phenotypic features. A 550 kb deletion at 15q24.1, including the whole SIN3A gene, was identified in S1, and a SIN3A nonsense rare variant (p.Arg471*) was detected in S2. Conclusion: These findings lead us to propose a link between SIN3A defects and CHH, especially in syndromic cases, based on these two patients with overlapping phenotypes of WITKOS and CHH.

Case report: Novel SIN3A loss-of-function variant as causative for hypogonadotropic hypogonadism in Witteveen–Kolk syndrome

“…Altogether, the evidence from patients with WITKOS and animal model studies has allowed to suggest that alterations in cortical expansion would be a direct consequence of SIN3A haploinsufficiency, leading to a broad range of neurodevelopmental disorders. An impaired expression in the structures originating the olfactory bulb and GnRH neurons can explain the reproductive and olfactory phenotypes observed in our patient and another case recently reported with WITKOS and Kallmann syndrome (Schnoll et al, 2023).…”

“…Pubertal delay, cryptorchidism, and micropenis, which can be due to hypogonadotropic hypogonadism, have been reported in patients with WITKOS due to 15q24 microdeletions ( Cushman et al, 2005 ; Magoulas and El-Hattab, 2012 ; Schnoll et al, 2023 ). The shortest region of overlap contains eight disease-related genes: COX5A , CYP11A1 , EDC3 , MAN2C1 , MPI , SEMA7A , SIN3A , and STRA6 .…”

“…Additionally, no clinically significant variants were found in the 96 candidate genes that we selected, according to the literature evidence linking them with hypogonadotropic hypogonadism. Interestingly, defects in SIN3A have recently been associated with syndromic congenital hypogonadotropic hypogonadism in two male patients with WITKOS, one of them with a 550-kb deletion at 15q24.1 and another with a nonsense rare variant in the N-terminal region of SIN3A ( Schnoll et al, 2023 ). Altogether, these data indicate that SIN3A haploinsufficiency could underlie the reproductive phenotype in patients with overlapping phenotypes of WITKOS and Kallmann syndrome.…”

“…In many of these syndromes, the reproductive phenotype remains underdiagnosed, with the clinical focus driven to the complex symptomatology. Recently, it has been suggested that hypogonadotropic hypogonadism may overlap with Witteveen–Kolk syndrome (WITKOS, OMIM #613406) ( Liu and Mapow, 2020 ; Schnoll et al, 2023 ).…”

A Witteveen-Kolk Syndrome Patient with Reflux Disease and a de novo Deletion of the SIN3A Gene

“…To date, cardiac abnormalities in patients with WITKOS have been reported in 4 different studies, which clearly state that cardiac examination was performed in the patients. These findings are atrial septal defect in 3 patients [5,6], ventricular septal defect in 1 patient [7], and Tetralogy of Fallot in 1 patient [8]. Our study also indicates that cardiac abnormalities could be a more common clinical feature than reported in WITKOS patients.…”