Differences in sex development

Gene: HHAT

After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains Amber. Additional comments from reviewing GLHs: 'Insufficient evidence to promote to green'

Created: 31 Jan 2023, 4:46 p.m. | Last Modified: 31 Jan 2023, 4:46 p.m.

Panel Version: 3.2

Green List (high evidence)

Comment on list classification: Promoting from red to amber but with a recommendation for green rating following GMS review. 2 cases reported with 46, XY karyotype and sex reversal, plus a supportive mouse model.

Created: 17 Dec 2021, 7:26 p.m. | Last Modified: 17 Dec 2021, 7:26 p.m.

Panel Version: 2.53

Associated with Nivelon-Nivelon-Mabille syndrome #600092 (AR) in OMIM.

Now 2 cases reported of probands with 46, XY karyotype and sex reversal reported (PMID:24784881 and 33749989). 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 tho-rax, short and angel-shaped epiphyses of hands and feet) and midfac eretrusion, short columella with a groove at the base, prominent ears, long philtrum, depressed nasal bridge, everted lower lip, and a singlec entral incisor. She also has complete sex reversal (karyotype of 46, XY, normal internal organs including uterus and ovaries.)

Also PMID:30912300 - Abdel-Salam et al 2019 reports another family with severe microcephaly and skeletal dysplasia phenotype but without dwarfism and gonadal dysgenesis. Both sisters had a normal female karyotype (46, XX). WES found a homozygous missense (c.770T>C, p.[Leu257Pro]) HHAT.

Created: 17 Dec 2021, 7:25 p.m. | Last Modified: 17 Dec 2021, 7:25 p.m.

Panel Version: 2.52

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Nivelon-Nivelon-Mabille syndrome, OMIM:600092

Publications

• 24784881
• 30912300
• 33749989

Comment when marking as ready: Not associated with phenotype in OMIM or G2P. One variant reported in 46,XY DSD with chondrodysplasia, supportive animal and in vitro evidence also provided

Created: 2 Nov 2016, 12:48 p.m.

Red List (low evidence)

Testicular steroid defect with chondrodysplasia; very few cases at present

Created: 4 Feb 2016, 4:22 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• 24784881