Hereditary Neuropathy_CMT - isolated

Gene: NRG1

Red List (low evidence)

1 female with consanguineous parents with distal muscle weakness starting age 20, progressively worsening, described as a peripheral neuropathy. Has a homozygous missense, 23 hets in gnomad. Proband has a sister who is also mildly affected, cramps and numbness in legs and feet. She is also homozygous for the variant. All 8 healthy family members that were tested were either only het or were hom for the WT allele.

13 other hom variants were identified in the proband, 11 were ruled out based on homs in gnomad, genes associated with off phenotype conditions, or non-segregation within the family. 2 variants in ZFHX4 and DMTN did cosegregate with disease. These 2 gene have limited reports/functional studies for off phenotype conditions so the NRG1 variant was thought to be the best match.

In a homozygous null NGR1 zebrafish, the variant identified in this individual was not able to rescue the phenotype compared to WT.
Sources: Expert Review

Created: 5 May 2022, 10:05 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Peripheral neuropathy MONDO:0005244

Publications

• 35485770

Comment on list classification: Red for peripheral neuropathy (single family reported)
Amber for Hirschsprung disease

Created: 5 May 2022, 2:05 a.m. | Last Modified: 5 May 2022, 2:05 a.m.

Panel Version: 0.13799

Red List (low evidence)

1 female with consanguineous parents with distal muscle weakness starting age 20, progressively worsening, described as a peripheral neuropathy. Has a homozygous missense, 23 hets in gnomad. Proband has a sister who is also mildly affected, cramps and numbness in legs and feet. She is also homozygous for the variant. All 8 healthy family members that were tested were either only het or were hom for the WT allele.

13 other hom variants were identified in the proband, 11 were ruled out based on homs in gnomad, genes associated with off phenotype conditions, or non-segregation within the family. 2 variants in ZFHX4 and DMTN did cosegregate with disease. These 2 gene have limited reports/functional studies for off phenotype conditions so the NRG1 variant was thought to be the best match.

In a homozygous null NGR1 zebrafish, the variant identified in this individual was not able to rescue the phenotype compared to WT.

Created: 5 May 2022, 1:53 a.m. | Last Modified: 5 May 2022, 1:53 a.m.

Panel Version: 0.13795

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Peripheral neuropathy MONDO:0005244

Publications

• 35485770

I don't know

Has been reported as a Hirschsprung disease susceptibility loci, with common, low-penetrance polymorphisms that contribute only partially to risk and can act as genetic modifiers. There are also two publications with rare variants reported in this gene (at least one de novo) and supporting in vitro functional assays. A null zebrafish model was also supportive of a role in Hirschsprung disease.
Sources: Expert list

Created: 3 Jul 2020, 4:53 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Hirschsprung disease

Publications

• 22574178
• 21706185
• 28190554