THU211 Novel SIN3A Loss-Of-Function Variant As Potentially Pathogenic For Hypogonadotropic Hypogonadism In Witteveen-Kolk Syndrome

Abstract

Abstract Disclosure: L.M. Correa Brito: None. A.C. Keselman: None. N.M. Sanguineti: None. P.A. Scaglia: None. M. Esnaola Azcoiti: None. F. Villegas: None. M. Maier: None. I. Bergada: None. M.G. Ropelato: None. R.A. Rey: None. Witteveen-Kolk Syndrome (WITKOS, MIM #613406) is an autosomal dominant disorder characterized by short stature, typical facial dysmorphism, microcephaly and mild intellectual disability, initially associated with 15q24 microdeletions encompassing SIN3A gene. Subsequently, WITKOS was found in individuals with loss-of-function (LOF) variants in SIN3A. Central or hypogonadotropic hypogonadism (HH) has been described in patients with WITKOS due to 15q24 microdeletions, but whether HH was due to haploinsufficiency of SIN3A or of any of the other five genes located in the shortest region of overlap (∼260 kb) of 15q24 could not be ascertained. A 6-year-old girl was referred to us for short stature. She had a history of intrauterine growth retardation and presented with microcephaly, broad forehead, wide nasal base, prominent nasal bridge, short philtrum, overfolded helix, clinodactyly of the 5th finger, joint laxity, neurodevelopmental delay, attention deficit hyperactivity disorder (ADHD), sensorineural hearing impairment, bicuspid aortic valve and ulcerative proctitis. She was treated with recombinant growth hormone, with good response. At the age of 14, she showed absence of thelarche and was evaluated for delayed puberty. Serum estradiol was undetectable, and gonadotropins were low after a GnRH infusion test (LH basal 0.2 IU/L, peak 0.7 IU/L; FSH basal 0.1 IU/L, peak 0.6 IU/L). HH was diagnosed. An MRI scan revealed a bilateral agenesis of the olfactory bulbs and olfactometry detected anosmia, leading to the clinical diagnosis of Kallmann syndrome (HH with anosmia). Whole exome sequencing (WES) identified a novel heterozygous frameshift variant, NM_001145358.2:c.3045_3046dup, NP_001138830.1:p.(Ile1016ArgfsTer6) in SIN3A. The insertion creates a frameshift expected to lead to a stop codon and a loss of function due to nonsense-mediated mRNA decay. Her mother, who had no history of HH, was while type for SIN3A. Unfortunately, his father was not available. The variant was absent in GnomAD, and has not been reported in dbSNP, ClinVar and Uniprot. It was classified as pathogenic according to the ACMG criteria, with a score of 10 points (8 points for PVS1_very strong, 1 point for PM2_supporting and 1 point for PP4_supporting). No other variant was found in 82 genes potentially related to HH. This is the first case report of a patient with WITKOS and HH carrying a pathogenic single nucleotide variant in SIN3A. Our results are strongly suggestive that HH in patients with WITKOS is due to SIN3A haploinsufficiency, thus ruling out a contiguous gene syndrome as causative for HH. Presentation: Thursday, June 15, 2023