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- Title
Rare variant of the epigenetic regulator SMCHD1 in a patient with pituitary hormone deficiency.
- Authors
Kinjo, Kenichi; Nagasaki, Keisuke; Muroya, Koji; Suzuki, Erina; Ishiwata, Keisuke; Nakabayashi, Kazuhiko; Hattori, Atsushi; Nagao, Koji; Nozawa, Ryu-Suke; Obuse, Chikashi; Miyado, Kenji; Ogata, Tsutomu; Fukami, Maki; Miyado, Mami
- Abstract
Isolated hypogonadotropic hypogonadism (IHH), combined pituitary hormone deficiency (CPHD), and septo-optic dysplasia (SOD) constitute a disease spectrum whose etiology remains largely unknown. This study aimed to clarify whether mutations in SMCHD1, an epigenetic regulator gene, might underlie this disease spectrum. SMCHD1 is a causative gene for Bosma arhinia microphthalmia syndrome characterized by arhinia, microphthalmia and IHH. We performed mutation screening of SMCHD1 in patients with etiology-unknown IHH (n = 31) or CPHD (n = 43, 19 of whom also satisfied the SOD diagnostic criteria). Rare variants were subjected to in silico analyses and classified according to the American College of Medical Genetics and Genomics guidelines. Consequently, a rare likely pathogenic variant, p.Asp398Asn, was identified in one patient. The patient with p.Asp398Asn exhibited CPHD, optic nerve hypoplasia, and a thin retinal nerve fiber layer, and therefore satisfied the criteria of SOD. This patient showed a relatively low DNA methylation level of the 52 SMCHD1-target CpG sites at the D4Z4 locus. Exome sequencing for the patient excluded additional variants in other IHH/CPHD-causative genes. In vitro assays suggested functional impairment of the p.Asp398Asn variant. These results provide the first indication that SMCHD1 mutations represent a rare genetic cause of the HH-related disease spectrum.
- Subjects
PITUITARY hormones; EPIGENETICS; HORMONE deficiencies; GENETIC mutation; BIOLOGICAL assay
- Publication
Scientific Reports, 2020, Vol 10, Issue 1, p1
- ISSN
2045-2322
- Publication type
Article
- DOI
10.1038/s41598-020-67715-x