Differences of Sex Development
Gene: HHAT
3 individuals from 3 families with 46, XY karyotype and sex reversal, with supportive mouse model reported in 24784881.
PMID:24784881 - Callier et al 2014 - report a family with 2 siblings with Disorder of Sex Development (DSD) and chondrodysplasia (Nivelon-Nivelon-Mabille syndrome). The first sibling (46,XY karyotype) displayed severe dwarfism with generalized chondrodysplasia, a narrow, bell-shaped thorax, micromelia, brachydactyly, severe microcephaly (-7.5 SD at age 16 (PMID:15578577) with cerebellar vermis hypoplasia, facial anomalies, hypoplastic irides, and coloboma of both optic discs. Complete gonadal dysgenesis ( including normal external female genitalia, lack of pubertal development, primary amenorrhea, and hypergonadotrophic hypogonadism) and intellectual disability is also noted. The second sibling (46,XX karyotype) had histologically normal ovaries and similar phenotypic abnormalities including severe dwarfism and generalized chondrodysplasia. Using WES a homozygous missense variant was found NM_001122834:c.860G>T:p.(Gly287Val) in HHAT in the first sibling which is in the conserved MBOAT domain. The parents were heterozygous. They also found that mice lacking functional Hhat show a similar phenotype as the syndromic 46,XY DSD patient including testicular dysgenesis and skeletal defects.
PMID: 33749989 - Pande et al 2021 - report multiple malformations in three pregnancies with a novel biallelic in-frame deletion, c.365_367del; (p.Thr122del), in exon 5 of HHAT in the living proband. She shows severe microphthalmia, microcephaly (−8 SD head circumference at age 7), skeletal dysplasia (narrow bell-shaped thorax, short and angel-shaped epiphyses of hands and feet) and midface retrusion, short columella with a groove at the base, prominent ears, long philtrum, depressed nasal bridge, everted lower lip, and a single central incisor. She also has complete sex reversal (karyotype of 46, XY, normal internal organs including uterus and ovaries.)
PMID: 35045414 - Mazen et al 2022 - report an Egyptian patient with 46,XY DSD (ambiguous genitalia and microcephaly) and a homozygous missense variant in HHAT, which segregated with the phenotype in the family.
Sources: Expert listCreated: 5 Dec 2024, 3:23 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Nivelon-Nivelon-Mabille syndrome, OMIM:600092
Publications
Gene: hhat has been classified as Green List (High Evidence).
Publications for gene: HHAT were set to PMID: 24784881, 33749989, 35045414
Gene: hhat has been classified as Green List (High Evidence).
gene: HHAT was added gene: HHAT was added to Differences of Sex Development. Sources: Expert list Mode of inheritance for gene: HHAT was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: HHAT were set to PMID: 24784881, 33749989, 35045414 Phenotypes for gene: HHAT were set to Nivelon-Nivelon-Mabille syndrome, OMIM:600092 Review for gene: HHAT was set to GREEN