NADSYN1

protein-coding

NAD synthetase 1, the group of MicroRNA protein coding host genes

Gene summary

Nicotinamide adenine dinucleotide (NAD) is a coenzyme in metabolic redox reactions, a precursor for several cell signaling molecules, and a substrate for protein posttranslational modifications. NAD synthetase (EC 6.3.5.1) catalyzes the final step in the biosynthesis of NAD from nicotinic acid adenine dinucleotide (NaAD).[supplied by OMIM, Apr 2004]

MANE transcript

NM_018161.5

Inheritance

ClinVar variants

P:20U:120B:24

Top phenotype

Vertebral, cardiac, renal, and limb defects syndrome 3

gnomAD constraint

pLI —, LoF o/e 0.7

Max pathogenic AF

—

Genomic locus

chr11:71,453,109-71,524,107

External References & Databases

Ensembl (ENSG00000172890)

Transcript & Mutation Effects

hg38 • Region Span ~71.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

vertebral, cardiac, renal, and limb defects syndrome 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030077

Submitter: G2P

congenital vertebral-cardiac-renal anomalies syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0020831

Submitter: Orphanet

vertebral, cardiac, renal, and limb defects syndrome 3LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0030077

Submitter: Labcorp Genetics (formerly Invitae)

vertebral, cardiac, renal, and limb defects syndrome 3MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0030077

Submitter: Ambry Genetics

vertebral, cardiac, renal, and limb defects syndrome 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030077

Submitter: PanelApp Australia

vertebral, cardiac, renal, and limb defects syndrome 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0030077

Submitter: ClinGen

The *NADSYN1* was first reported in association with autosomal recessive congenital NAD deficiency disorder (CNDD) in 2019 - Szot JO et al., PMID: PMID: 31883644. Since the initial report, multiple affected individuals from unrelated families with biallelic *NADSYN1* variants have been described. Affected individuals demonstrate a highly variable multisystem phenotype that includes vertebral, cardiac, limb, renal, and craniofacial abnormalities, among other developmental defects. Nine variants variants (missense, nonsense, frameshift) that have been reported in seven probands in four publications (PMID: 35491967, PMID: 36649848, PMID: 38357931, PMID: 31883644) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss-of-function. Although heterozygous *NADSYN1* variants have also been reported in at least nine individuals with congenital vertebral malformations and multisystem abnormalities, unaffected heterozygous relatives reported in subsequent studies and the potential influence of environmental factors on NAD levels leave the clinical significance and penetrance of heterozygous variants uncertain (PMID: 36649848, PMID: 37300479). Functional characterization of disease-associated missense variants demonstrated significantly reduced *NADSYN1*-dependent NAD synthetase activity, with several variants exhibiting near-complete or complete loss of enzymatic activity (PMID: 38357931). Consistent with these findings, disruption of *NADSYN1* in human cell lines results in impaired maintenance of intracellular NAD levels under conditions of limited nicotinamide availability and broad alterations in cellular metabolism (PMID: 38132878). Additionally, Nadsyn1 knockout mice develop embryonic lethality and multisystem congenital malformations under conditions of limited maternal NAD precursor availability, including abnormalities of the kidneys, eyes, lungs, heart, vertebrae, palate, abdominal wall, and neural tube, recapitulating major features of the human disorder. Supplementation with NAD precursors capable of bypassing the *NADSYN1*-dependent metabolic block, including nicotinamide (NAM) and nicotinamide mononucleotide (NMN), prevented or reduced adverse developmental outcomes, further supporting NAD deficiency as the underlying disease mechanism (PMID: 38357931). In summary, there is definitive evidence supporting the relationship between *NADSYN1* and autosomal recessive congenital NAD deficiency disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen IEM GCEP at the meeting on September 25, 2026 (SOP Version 12).

Clinical Genomic Database (CGD)

Vertebral, cardiac, renal, and limb defects syndrome 3AR

Manifestation: Cardiovascular; Craniofacial; Gastrointestinal; Musculoskeletal; Pulmonary; Renal

Intervention: Cardiovascular

Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management

Refs: 31883644

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NADSYN1 variants in ClinVar

9 Conditions Cataloged

Inborn genetic diseasesTotal: 90

Vertebral, cardiac, renal, and limb defects syndrome 3Total: 29

not providedTotal: 27

NADSYN1-related disorderTotal: 20

not specifiedTotal: 17

Congenital NAD deficiency disorderTotal: 6

ChondrodysplasiaTotal: 2

Neurodevelopmental delayTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018161.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	13 clinvar	4 clinvar	19
missense	1 clinvar	6 clinvar	108 clinvar	6 clinvar	1 clinvar	122
nonsense	3 clinvar	3 clinvar	1 clinvar			7
start loss						0
frameshift	1 clinvar	2 clinvar				3
splice donor/acceptor (+/-2bp)	2 clinvar	2 clinvar	9 clinvar			13
Total	7	13	120	19	5	164

Highest pathogenic variant AF is 0.0011753743

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 53 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018161.5	RefSeq	NP_060631.2	21	MANE Select
ENST00000319023.7	Ensembl	ENSP00000326424.2	21	MANE Select
ENST00000525200.5	Ensembl	ENSP00000432129.1	9	Standard
ENST00000525593.5	Ensembl	ENSP00000433612.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Nicotinate and nicotinamide metabolism - Homo sapiens (human)
2-Hydroxyglutric Aciduria (D And L Form)
Nicotinate and Nicotinamide Metabolism
Homocarnosinosis
Hyperinsulinism-Hyperammonemia Syndrome

Biological Process

NAD biosynthetic process
NAD metabolic process

Molecular Function

NAD+ synthase (glutamine-hydrolyzing) activity
glutaminase activity
protein binding
ATP binding

Cellular Component

cytoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000319023
Coding exons: 21
Length: 70999
Individuals with no LoFs: 125646
Homozygous LoFs: 0
Heterozygous LoFs: 102
Defined: 125748
p: 0.000406

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.710	407	449	0.906	0.0000282	4612
Missense (PolyPhen)		156	171.98	0.90708		1773
Synonymous	-1.01	210	192	1.09	0.0000145	1351
Loss of Function	1.89	32	45.8	0.699	0.00000243	476

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00038	0.00037	rare
Latino/Admixed American	0.00029	0.00029	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00038	0.00038	rare
Finnish	0.00043	0.00042	rare
European (Non-Finnish)	0.00041	0.00040	rare
South Asian	0.00076	0.00075	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Recessive Scores

pRec: 0.101

Intolerance Scores

LoFtool: 0.258
RVIS EVS: -0.21
RVIS percentile EVS: 37.78

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.987

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium