Monogenic hearing loss

Gene: GRHL2

Green List (high evidence)

Comment on mode of inheritance: While there are several individuals reported with monoallelic GRHL2 variants and hearing loss, only 1/4 families reported with biallelic variants presented with hearing loss. Hence, the MOI for Monogenic hearing loss should be changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted.

Created: 22 May 2026, 10:25 a.m. | Last Modified: 22 May 2026, 10:25 a.m.

Panel Version: 6.12

BIALLELIC CASES:
PMID: 25152456 Petros et al., 2013
2 consanguineous Kuwaiti families with 6 total affected individuals with ectodermal dysplasia. Shared features: nail dystrophy or nail loss, marginal palmoplantar keratoderma, hypodontia, enamel hypoplasia, oral hyperpigmentation, short stature (≤25th percentile), and dysphagia. Patients in family ED-01 also presented with sensorineural deafness. ED-01 members were homozygous for GRHL2 c.1192T>C (p.Tyr398His), and ED-02 were homozygous for c.1445T>A (p.Ile482Lys).

PMID: 27612988 Walne et al., 2016
Report of 2 consanguineous families from Kuwait and Turkey.
Family 9: index patient homozygous for GRHL2 c.1445T>A p.Ile482Lys
Family 10: index patient homozygous for GRHL2 c.1213C>A p.Pro405Thr
Shared phenotype of the 2 probands: abnormal dentition, nail dystrophy, abnormal skin pigmentation, growth restriction (short stature). No mention of hearing loss.

MONOALLELIC CASES:
PMID: 12393799 Peters et al., 2002
Large American family with an autosomal dominant form of progressive non-syndromic sensorineural hearing loss. Variant c.1609-1610insC in GRHL2 (old name TFCP2L3) segregated with hearing loss.

PMID: 23813623 Vona et al., 2013
Large pedigree with post-lingual hearing loss with a highly variable age of onset and progression - segregated with a heterozygous non-classical splice site mutation in GRHL2: c.1258-1G>A, p.Gly420Glufs*111.

PMID: 27911912 Iwasa et al., 2016
3 Japanese families with AD hearing loss and heterozygous GRHL2 variants (2 missense, 1 frameshift)

PMID: 32048449 Wu et al., 2020
Han Chinese family with AD non-syndromic deafness, a het GRHL2 p.R426X variant segregated with hearing loss.

Created: 22 May 2026, 10:22 a.m. | Last Modified: 22 May 2026, 10:39 a.m.

Panel Version: 6.12

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Ectodermal dysplasia/short stature syndrome, OMIM:616029

Publications

• 12393799
• 23813623
• 25152456
• 27612988
• 27911912
• 32048449

Green List (high evidence)

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

New review confirms gene status and mode of inheritance; no changes required.

Created: 11 Oct 2018, 1:47 p.m.

Comment on mode of inheritance: AD is indicated by OMIM, but AR by reviewer.

Created: 17 Feb 2016, 3:41 p.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
#608641:Deafness, autosomal dominant 28[Deafness, sensorineuralMild to moderate hearing loss across most frequenciesSevere loss in the higher frequencies by the fifth decade]; #616029:Ectodermal dysplasia/short stature syndrome[Short stature; Sensorineural deafness in early infancy (in some patients); Hyperpigmentation of the oral mucosaHyperpigmentation of the tongue; Delayed dentitionHypodontiaEnamel hypoplasia; Bronchial asthma (in some patients); Dysphagia (in some patients)Esophageal strictures (in some patients); Keratoderma of margins of palms and solesFocal hyperkeratosis of dorsum of hands and feet; Acanthosis, mildHyperkeratosis, mild; Dystrophic nailsAbsent nails]

Comment when marking as ready: Expert review and OMIM confirmed

Created: 29 Jan 2016, 3:32 p.m.