Differences of Sex Development

Gene: HHAT

Green List (high evidence)

HHAT (hedgehog acyltransferase)
EnsemblGeneIds (GRCh38): ENSG00000054392
EnsemblGeneIds (GRCh37): ENSG00000054392
OMIM: 605743, Gene2Phenotype
HHAT is in 7 panels

1 review

Chirag Patel (Genetic Health Queensland)

Green List (high evidence)

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 list
Created: 5 Dec 2024, 3:23 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Nivelon-Nivelon-Mabille syndrome, OMIM:600092

Publications

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Expert list
Phenotypes
  • Nivelon-Nivelon-Mabille syndrome, OMIM:600092
OMIM
605743
Clinvar variants
Variants in HHAT
Penetrance
None
Publications
Panels with this gene

History Filter Activity

8 Dec 2024, Gel status: 3

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Gene: hhat has been classified as Green List (High Evidence).

8 Dec 2024, Gel status: 3

Set publications

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Publications for gene: HHAT were set to PMID: 24784881, 33749989, 35045414

5 Dec 2024, Gel status: 3

Entity classified by Genomics England curator

Chirag Patel (Genetic Health Queensland)

Gene: hhat has been classified as Green List (High Evidence).

5 Dec 2024, Gel status: 1

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes

Chirag Patel (Genetic Health Queensland)

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