Bilateral congenital or childhood onset cataracts

Gene: GEMIN4

Green List (high evidence)

The rating of this gene has been updated to Green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.

Created: 24 Feb 2025, 5:19 p.m. | Last Modified: 24 Feb 2025, 5:19 p.m.

Panel Version: 6.6

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Green List (high evidence)

Comment on list classification: There are 12 unrelated families and three different GEMIN4 variants reported in the literature. Hence, this gene can be promoted to green rating in the next GMS update.

Created: 19 Jul 2024, 8:26 p.m. | Last Modified: 19 Jul 2024, 8:29 p.m.

Panel Version: 4.17

PMID:35861185 provided a retrospective review of 16 patients from 11 unrelated Saudi consanguineous families with GEMIN4 variants., of which five patients were previously reported. Only two missense homozygous pathogenic variants (p.Pro105Leu and p.Trp818Arg) were reported in these patients, which suggests founder effect. All patients shared global developmental delay with variable ophthalmological, renal, and skeletal manifestations. Cataract was present in all 16 patients.

PMID:35052432 reported the identification of a novel homozygous variant (p.His147Arg) in two siblings from a consanguineous Saudi family. Both of them presented with global developmental delay, seizures, microcephaly and cataract.

This gene has been associated with relevant phenotypes in OMIM (MIM #617913) and Gene2Phenotype (with 'strong' rating on the DD panel and 'limited' rating on the eye panel).

Created: 19 Jul 2024, 8:23 p.m. | Last Modified: 19 Jul 2024, 8:23 p.m.

Panel Version: 4.14

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities, OMIM:617913

Publications

• 35052432
• 35861185

I don't know

5 individuals from 3 consanguineous families reported originally; same homozygous missense in all raising concern about this being a founder variant. Another individual reported with different variant as part of a study reporting large number of novel/emerging genes in consanguineous cohort.

Created: 8 Jul 2020, 7:42 a.m. | Last Modified: 8 Jul 2020, 7:42 a.m.

Panel Version: 2.6

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities, 617913

Publications

• 25558065
• 27878435

I don't know

The rating of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 8 Mar 2022, 9:09 a.m. | Last Modified: 8 Mar 2022, 9:09 a.m.

Panel Version: 2.98

On re-reviewing this gene, the mouse model was not a knockout gene model of GEMIN4. PMID: 30237576 is a new publication that describes another case with the same variant as that reported by PMID: 25558065. The affected individual is from the same region as the previous publication. Therefore, there is insufficient evidence to support a gene-disease status and this gene should be downgraded from Green to Amber at the next review.

Created: 15 Dec 2020, 2:26 p.m. | Last Modified: 15 Dec 2020, 2:26 p.m.

Panel Version: 2.31

Comment on list classification: Promoted from Red to Green based on previous review.

Created: 2 Oct 2019, 1:50 p.m. | Last Modified: 2 Oct 2019, 1:50 p.m.

Panel Version: 1.34

GEMIN4 is associated with a phenotype on OMIM but not Gene2Phenotype. It is an amber gene on the ID panel (code 285, version 2.1017). PMID: 25558065 reported on 5 affected patients from 3 unrelated consanguineous Saudi families with neurodevelopmental disorder, microcephaly cataracts and renal abnormalities. PMID: 27878435 reported on a different family with a different variant that was previously reported. The same paper also performed mouse studies and found that the gene is down regulated in key gene knockout mice with lens defects. Therefore, there is enough evidence for this gene to be green.

Created: 28 Aug 2019, 3:43 p.m. | Last Modified: 28 Aug 2019, 3:43 p.m.

Panel Version: 1.32

Publications

• 30237576