Skeletal dysplasia

Gene: NMNAT1

I don't know

Comment on list classification: As two of the three reported families were distantly related, this gene should only be rated AMBER with the current evidence. However, 'watchlist' tag was added to review the rating in light of new evidence in the future.

Created: 25 May 2023, 7 p.m. | Last Modified: 25 May 2023, 7 p.m.

Panel Version: 4.3

The 'cnv' tag was added as two of the reported cases harboured duplication variants in homozygous state and the third case harboured duplication variant together with a splicing variant.

Created: 25 May 2023, 6:58 p.m. | Last Modified: 25 May 2023, 6:58 p.m.

Panel Version: 4.2

PMID:32533184 reported two distantly related families homozygous for 7.4-kb duplication involving the last 2 exons of the NMNAT1 gene (chr1:10,036,359-10,043,727, GRCh37).

PMID:33668384 reported a 2-year-old girl compound heterozygous for the duplication and with a splicing variant (c.439+5G>T).

These patients presented with a severe form of spondylo-epiphyseal dysplasia, sensorineural hearing loss, intellectual disability, Leber congenital amaurosis and several brain abnormalities.

This gene has been associated with relevant phenotypes in OMIM (MIM #619260).

Created: 25 May 2023, 6:55 p.m. | Last Modified: 25 May 2023, 6:55 p.m.

Panel Version: 4.2

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Spondyloepiphyseal dysplasia, sensorineural hearing loss, intellectual developmental disorder, and Leber congenital amaurosis, OMIM:619260

Publications

• 32533184
• 33668384

Green List (high evidence)

The association with LCA is well established.

New report of a syndromic LCA disorder and note also unusual variant type. Three families, but two are distantly related (shared haplotype). The affected children in those two families were homozygous for 7.4-kb duplication involving the last 2 exons of the NMNAT1 gene, spanning the beginning of intron 3 to the middle of the 3-prime UTR (chr1:10,036,359-10,043,727, GRCh37). The third affected individual was compound het for the duplication and a splicing variant.
Sources: Literature

Created: 17 Apr 2021, 7:39 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Spondyloepiphyseal dysplasia, sensorineural hearing loss, intellectual disability, and Leber congenital amaurosis (SHILCA), MIM#619260

Publications

• 32533184

Variants in this GENE are reported as part of current diagnostic practice