Disorders of sex development

Gene: HHAT

Amber List (moderate evidence)

HHAT (hedgehog acyltransferase)
EnsemblGeneIds (GRCh38): ENSG00000054392
EnsemblGeneIds (GRCh37): ENSG00000054392
OMIM: 605743, Gene2Phenotype
HHAT is in 4 panels

3 reviews

Eleanor Williams (Genomics England Curator)

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

Sarah Leigh (Genomics England Curator)

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.

John Achermann (UCL Institute of Child Health)

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

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
Phenotypes
  • 46,XY DSD with chondrodysplasia
  • Nivelon-Nivelon-Mabille syndrome, OMIM:600092
Tags
Q4_21_rating
OMIM
605743
Clinvar variants
Variants in HHAT
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

17 Dec 2021, Gel status: 2

Set Phenotypes

Eleanor Williams (Genomics England Curator)

Phenotypes for gene: HHAT were changed from 46,XY DSD with chondrodysplasia to 46,XY DSD with chondrodysplasia; Nivelon-Nivelon-Mabille syndrome, OMIM:600092

17 Dec 2021, Gel status: 2

Set publications

Eleanor Williams (Genomics England Curator)

Publications for gene: HHAT were set to 24784881

17 Dec 2021, Gel status: 2

Entity classified by Genomics England curator

Eleanor Williams (Genomics England Curator)

Gene: hhat has been classified as Amber List (Moderate Evidence).

17 Dec 2021, Gel status: 1

Added Tag

Eleanor Williams (Genomics England Curator)

Tag Q4_21_rating tag was added to gene: HHAT.

21 Dec 2016, Gel status: 1

panel promoted to version 1

Sarah Leigh (Genomics England Curator)

Promoted to V1 21/12/2016

2 Nov 2016, Gel status: 1

Gene classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

This gene has been classified as Red List (Low Evidence).

2 Nov 2016, Gel status: 0

Set Phenotypes

Sarah Leigh (Genomics England Curator)

Phenotypes for HHAT were set to 46,XY DSD with chondrodysplasia

2 Nov 2016, Gel status: 0

Set publications

Sarah Leigh (Genomics England Curator)

Publications for HHAT were set to 24784881

23 May 2016, Gel status: 0

Approved Gene

Sarah Leigh (Genomics England Curator)

This proposed gene was validated and added to this panel

4 Feb 2016, Gel status: 0

Added New Source

John Achermann (UCL Institute of Child Health)

HHAT was added to Disorders of sex developmentpanel. Sources: Expert Review

4 Feb 2016, Gel status: 0

Created

John Achermann (UCL Institute of Child Health)

HHAT was created by John Achermann