Heterotaxy
Gene: NODAL
NODAL is a good biological candidate for heterotaxy disorders, and this is supported by animal models. The gene is depleted for LoF variants in gnomad.
The missense variants reported in PMIDs 9354794 and 19064609 are present at a high population frequency in gnomad, including some in homozygous case: their association with disease is DISPUTED.
A total of at least 7 families reported with severe CHD and high impact variants (stop gain, frameshift and canonical splice site). However, almost invariably these were inherited from unaffected or questionably affected parents (e.g. self reports of heart murmur in childhood), raising questions about whether these variants contribute to disease under a monogenic or polygenic model and/or about penetrance.
Discussed at GenCC on 13/9/2022 and agreed on MODERATE assessment.Created: 12 Sep 2022, 10:14 p.m. | Last Modified: 12 Sep 2022, 10:14 p.m.
Panel Version: 1.20
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Heterotaxy, visceral, 5 (MIM#270100)
Publications
Minimal reports and variants in original publications present in gnomAD at a higher than expected frequency, originally concluded to be due to incomplete penetrance.
PMID: 9354794 (1997): R183Q reported in affected daughter and unaffected mother. (26 hets; 1 hom in gnomAD)
PMID: 19064609 (2009): Reported 4 missense, 1 indel and 2 splice site variants. G260R also found in unaffected individual, concluded to have incomplete penetrance (80 hets in gnomAD); R275C (13 hets in gnomAD); E203K (113 hets and 1 hom)
Sources: Expert ReviewCreated: 11 May 2020, 3:21 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
Heterotaxy, visceral, 5 (MIM#270100)
Publications
Publications for gene: NODAL were set to 9354794; 19064609
Mode of inheritance for gene: NODAL was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Gene: nodal has been classified as Amber List (Moderate Evidence).
Gene: nodal has been classified as Red List (Low Evidence).
Gene: nodal has been classified as Red List (Low Evidence).
Tag disputed tag was added to gene: NODAL.
gene: NODAL was added gene: NODAL was added to Heterotaxy. Sources: Expert Review Mode of inheritance for gene: NODAL was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: NODAL were set to 9354794; 19064609 Phenotypes for gene: NODAL were set to Heterotaxy, visceral, 5 (MIM#270100) Review for gene: NODAL was set to RED