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Fetal anomalies

Gene: NMNAT2

Amber List (moderate evidence)
NMNAT2 (nicotinamide nucleotide adenylyltransferase 2)
EnsemblGeneIds (GRCh38): ENSG00000157064
EnsemblGeneIds (GRCh37): ENSG00000157064
OMIM: 608701, Gene2Phenotype
NMNAT2 is in 6 panels

3 reviews

Rhiannon Mellis (Great Ormond Street Hospital)

I don't know

This gene and phenotype were reviewed during a meeting on 21st July 2022 between representatives of the North Thames and Central & South R21 testing GLHs.
Clinical review and curation was performed by Lyn Chitty, Alison Male, Rhiannon Mellis (North Thames GLH), and Stephanie Allen, Denise Williams, Esther Kinning and Anna de Burca (Central & South GLH).

Outcome of review: Note previous review describing 2 sibs with fetal akinesia, hydrops etc. and a mouse model. One more family reported now with some phenotypic overlap but not exact match. Support keeping Amber for now, pending more evidence.

Not rated Green on any other PanelApp panel(s) at present.

Details of review: The fetal case in Tolusso et al 2021 (PMID: 33442022) had Multiple brain malformations, hydrops, small chest, hepatomegaly, decreased muscle mass, small kidneys, and oligohydramnios detected by ultrasound at 20 + 5 weeks gestation. Parents later had another pregnancy affected by similar anomalies and targeted prenatal diagnostic testing confirmed the same NMNAT2 variants in this second fetus.


The fetal case in Tolusso et al 2021 had Multiple brain malformations, hydrops, small chest, hepatomegaly, decreased muscle mass, small kidneys, and oligohydramnios detected by ultrasound at 20 + 5 weeks gestation. Parents later had another pregnancy affected by similar anomalies and targeted prenatal diagnostic testing confirmed the same NMNAT2 variants in this fetus.
Created: 1 Aug 2022, 5:24 p.m. | Last Modified: 1 Aug 2022, 5:24 p.m.
Panel Version: 1.880

Phenotypes
Hydrops fetalis; brain malformation; oligohydramnios

Publications

Created: 1 Aug 2022, 5:24 p.m.
Last Modified: 1 Aug 2022, 5:24 p.m.
Panel version: 1.880

Rebecca Foulger (Genomics England curator)

Comment on list classification: NMNAT2 was added to the Fetal anomalies panel and rated Green by Michael Coleman (University of Cambridge). Not yet associated with a disorder in OMIM or Gene2Phenotype. Currently 2 fetal siblings (1 case) in PMID:31136762 and a mouse model. Rated as Amber awaiting clinical feedback and further cases.
Created: 17 Sep 2019, 9:38 a.m. | Last Modified: 17 Sep 2019, 9:38 a.m.
Panel Version: 0.344
PMID:31132363, Huppke et al., 2019 report a homozygous missense variant (c.281C>T (T94M) in NMNAT2 in 2 siblings with childhood onset polyneuropathy with erythromelalgia: symptoms were first seen age 4.
Created: 17 Sep 2019, 9:34 a.m. | Last Modified: 17 Sep 2019, 9:34 a.m.
Panel Version: 0.343
PMID:31136762 (Lukacs et al., 2019) report 2 stillborn siblings with fetal akinesia deformation sequence (FADS), and symptons including severely reduced skeletal muscle mass and hydrops fetalis. Exome sequencing identified compound heterozygous NMNAT2 variant alleles in both cases: maternally-inherited c.403dupC, p.Q135Pfs*44, and paternally-inherited missense variant c.695G>A,p.R232Q. A similar phenotype (though not identical) was reported in mouse (Hicks et al., 2012: PMID:23082226).
Created: 17 Sep 2019, 9:33 a.m. | Last Modified: 17 Sep 2019, 9:33 a.m.
Panel Version: 0.343
Created: 17 Sep 2019, 9:33 a.m.
Last Modified: 17 Sep 2019, 9:33 a.m.
Panel version: 0.343

Michael Coleman (University of Cambridge)

Green List (high evidence)

Closely related phenotype in homozygous null mouse (PMID 23946398)
Sources: Research
Created: 11 Sep 2019, 10:01 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
hydrops fetalis; cystic hygroma; bilateral hypoplastic lungs; hydrocephalus; hypoplastic cerebellum; severely reduced skeletal muscle mass or absence; flexion contractures of all extremities; micrognathia; cleft palate; hydropic placenta

Publications

Created: 11 Sep 2019, 10:01 p.m.

Panel version: 0.341

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
Phenotypes
  • hydrops fetalis
  • cystic hygroma
  • bilateral hypoplastic lungs
  • hydrocephalus
  • hypoplastic cerebellum
  • severely reduced skeletal muscle mass or absence
  • flexion contractures of all extremities
  • micrognathia
  • cleft palate
  • hydropic placenta
OMIM
608701
Clinvar variants
Variants in NMNAT2
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

9 Aug 2022, Gel status: 2

Set publications

Arina Puzriakova (Genomics England Curator)

Publications for gene: NMNAT2 were set to 31136762; 31132363; 23082226

17 Sep 2019, Gel status: 2

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: nmnat2 has been classified as Amber List (Moderate Evidence).

17 Sep 2019, Gel status: 0

Set publications

Rebecca Foulger (Genomics England curator)

Publications for gene: NMNAT2 were set to PMID: 31136762

11 Sep 2019, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Michael Coleman (University of Cambridge)

gene: NMNAT2 was added gene: NMNAT2 was added to Fetal anomalies. Sources: Research Mode of inheritance for gene: NMNAT2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NMNAT2 were set to PMID: 31136762 Phenotypes for gene: NMNAT2 were set to hydrops fetalis; cystic hygroma; bilateral hypoplastic lungs; hydrocephalus; hypoplastic cerebellum; severely reduced skeletal muscle mass or absence; flexion contractures of all extremities; micrognathia; cleft palate; hydropic placenta Penetrance for gene: NMNAT2 were set to Complete Review for gene: NMNAT2 was set to GREEN