Further description of two patients with biallelic variants in NADSYN1 in association with cardiac and vertebral anomalies

Abstract

Congenital nicotinamide adenine dinucleotide (NAD) deficiency disorders are associated with pathogenic variants in the genes NADSYN1, HAAO, and KYNU. These disorders overlap with the anomalies present in vertebral, anal, cardiac, tracheoesophageal, radial and renal, and limb anomalies (VATER/VACTERL) association and often result in premature death. Children who survive typically have developmental delays or intellectual disability. Here, we describe two patients with compound heterozygous variants in NADSYN1 who presented with cardiac and vertebral defects overlapping with the VATER/VACTERL association, although the patients did not satisfy criteria for the diagnosis of VATER/VACTERL due to their lack of limb anomalies and significant renal anomalies. One patient survived into childhood with developmental delays and may represent an expansion of the survival data for NADSYN1-associated NAD deficiency disorders. Interestingly, one patient had hypoplastic left heart syndrome (HLHS) and one had an aortic coarctation and transverse hypoplasia of the aortic arch, suggesting that NADSYN1 sequencing should be performed in children presenting with congenital anomalies related to VATER/VACTERL association and with HLHS and aortic arch abnormalities.

Clinical heterogeneity of NADSYN1‐associated VCRL syndrome

“…This variant has been previously reported, and functional analysis performed proved its pathogenicity, causing a reduction in NAD enzymatic activity 3 . Its presence at the homozygous/compound heterozygous state with either another missense, frameshift, or nonsense variant in trans, can be associated with both very severe and mild phenotypes 3,9 . No mutational hotspot has been found, but the localisation of the variants suggested they all impact critical functional domains of NADSYN1 protein 8 .…”

“…In total, 16 individuals carrying biallelic NADSYN1 variants have been reported 3,8,9 . The clinical phenotype described in NADSYN1 ‐Associated NAD Deficiency Disorder was initially presented as very severe (five perinatal lethal presentations) 3 .…”

“…The molecular screening of a VACTERL cohort allowed to identify nine cases with pathogenic variants in NADSYN1 , thus expanding the spectrum to living patients with vertebral segmentation defects and a milder phenotype 8 . Two recent cases also had cardiac and vertebral anomalies, in whom one survived with a mild developmental delay 9 …”

Viewing teratogens through the lens of nicotinamide adenine dinucleotide (NAD+)

“… b Adapted from Shi et al, 2017, Szot et al, 2020, Ehmke et al, 2020, Schüle et al, 2021, Szot et al, 2021, L. Bird, personal communication, September 14, 2021, Mark, 2022, Kortbawi et al, 2022. …”

“…To date, there have been 24 patients described with biallelic variants in NAD+ Synthesis pathway genes, specifically HAAO , KYNU , and NADSYN1 (Shi et al, 2017; Szot et al, 2020; Ehmke et al, 2020; Schüle et al, 2021; Szot et al, 2021; L. Bird, personal communication, September 14, 2021, Kortbawi et al, 2022). It is important to note that although this is a genetic disorder, the end result is decreased production of NAD+, as shown in research measurement of human NAD levels and mouse and yeast models of the specific variants seen in patients (Shi et al, 2017, Szot et al, 2020, Szot et al, 2021).…”