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Severe microcephaly

Gene: HHAT

Amber List (moderate evidence)

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

2 reviews

Eleanor Williams (Genomics England Curator)

Green List (high evidence)

Comment on list classification: Promoting from red to amber, with a recommendation for green rating following GMS review. 3 cases with microcephaly progressing to severe microcephaly reported.
Created: 17 Dec 2021, 7:16 p.m. | Last Modified: 17 Dec 2021, 7:16 p.m.
Panel Version: 2.276
Associated with Nivelon-Nivelon-Mabille syndrome #600092 (AR) in OMIM.

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:30912300 - Abdel-Salam et al 2019 - report two siblings with progressive microcephaly (-6 SD at age 6 and age 3 for the 2 siblings respectively), early infantile onset seizures, and cerebellar vermis hypoplasia but notably without dwarfism and gonadal dysgenesis. Skeletal x-rays of both siblings showed enlarged epiphyses and metaphyses, thinning of the lateral 1/3 of clavicles and trapezoidal vertebral bodies. Both sisters had a normal female karyotype (46, XX). WES found a homozygous missense (c.770T>C, p.[Leu257Pro]) HHAT which is in the conserved MBOAT domain. Both parents were heterozygous for the variant.

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.)
Created: 17 Dec 2021, 6:46 p.m. | Last Modified: 17 Dec 2021, 7:11 p.m.
Panel Version: 2.161

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Nivelon-Nivelon-Mabille syndrome, OMIM:600092


Zornitza Stark (Australian Genomics)

I don't know

Two unrelated families reported. Clinical features include progressive microcephaly, cerebellar vermis hypoplasia, and skeletal dysplasia. Variable features include infantile-onset seizures, dwarfism, generalized chondrodysplasia, and micromelia.
Sources: Literature
Created: 9 Dec 2020, 7:35 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Nivelon-Nivelon-Mabille syndrome 600092



Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
  • Expert Review Amber
  • Literature
  • Nivelon-Nivelon-Mabille syndrome, OMIM:600092
Clinvar variants
Variants in HHAT
Panels with this gene

History Filter Activity

17 Dec 2021, Gel status: 2

Added Tag

Eleanor Williams (Genomics England Curator)

Tag Q4_21_rating tag was added to gene: HHAT.

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

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

Eleanor Williams (Genomics England Curator)

gene: HHAT was added gene: HHAT was added to Severe microcephaly. Sources: Literature Mode of inheritance for gene: HHAT was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: HHAT were set to 24784881; 30912300; 33749989 Phenotypes for gene: HHAT were set to Nivelon-Nivelon-Mabille syndrome, OMIM:600092