Paediatric or syndromic cardiomyopathy

Gene: NAXD

Green List (high evidence)

Comment on list classification: There are >10 unrelated patients reported with biallelic NAXD variants and with 'Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2' (MIM #618321). However, the disease has a variable presentation and cardiomyopathy was reported in four unrelated patients. As this panel includes syndromic cases, this gene can be considered for promotion to green rating in the next GMS update.

Created: 25 Aug 2025, 9:15 p.m. | Last Modified: 25 Aug 2025, 9:15 p.m.

Panel Version: 7.23

Comment on phenotypes: OMIM phenotype accessed on 25 August 2025.

Created: 25 Aug 2025, 9:12 p.m. | Last Modified: 25 Aug 2025, 9:12 p.m.

Panel Version: 7.22

PMID:30576410 (2019) reported six unrelated individuals with biallelic NAXD variants, and with encephalopathy precipitated by febrile illnesses. They all had severe neurological deterioration and died in early childhood. One of these six patients, who is a girl of Indian descent developed dilated cardiomyopathy and heart failure, and was identified with homozygous c.54_57delAAGA (p.Ala20Phefs*9) variant.

PMID: 32462209 (2020) reported a seven-year-old male patient that experienced rapid deterioration and after gastroenteritis and died suddenly. An autopsy imaging CT scan showed thickening of the myocardial wall and gross hypertrophic cardiomyopathy in the patient. His paternal uncle also died due to acute myocardial infarction at the age of 28. Biallelic variants (c.44delG/ p.Arg15Glnfs*3 & c.54_57delAAGA/ p.Ala20Phefs*9) were identified by WES in the patient and these variants are present in heterozygous state in the parents.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the 100,000 genomes project, of which one female patient with dilated cardiomyopathy was identified with homozygous variant in NAXD gene (c.54_57del/ p.Ala20PhefsTer9).

PMID:39822994 (2024) reported a 47-month-old male patient of Chinese descent that experienced a sharp deterioration after febrile illness, causing heart failure, cardiogenic shock, and ultimately death. This patient was diagnosed with myocarditis and dilated cardiomyopathy and was identified with compound heterozygous variants in NAXD gene (c.43C>T/ p.Arg15Ter & c.781G>T/ p.Gly261Cys).

This gene has been associated with MIM #618321 in OMIM, which mentions cardiomyopathy as one of the clinical presentations that is observed in some patients.
Sources: Literature

Created: 25 Aug 2025, 9:12 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2, OMIM:618321; NAD(P)HX dehydratase deficiency, MONDO:0034121

Publications

• 30576410
• 32462209
• 39472908
• 39822994