Birth defects occur in up to 3% of all live births and are the leading cause of infant death. Here we present five individuals from four unrelated families, individuals who share similar phenotypes with disease-causal bi-allelic variants in NADSYN1, encoding NAD synthetase 1, the final enzyme of the nicotinamide adenine dinucleotide (NAD) de novo synthesis pathway. Defects range from the isolated absence of both kidneys to multiple malformations of the vertebrae, heart, limbs, and kidney, and no affected individual survived for more than three months postnatally. NAD is an essential coenzyme for numerous cellular processes. Bi-allelic loss-of-function mutations in genes required for the de novo synthesis of NAD were previously identified in individuals with multiple congenital abnormalities affecting the heart, kidney, vertebrae, and limbs. Functional assessments of NADSYN1 missense variants, through a combination of yeast complementation and enzymatic assays, show impaired enzymatic activity and severely reduced NAD levels. Thus, NADSYN1 represents an additional gene required for NAD synthesis during embryogenesis, and NADSYN1 has bi-allelic missense variants that cause NAD deficiency-dependent malformations. Our findings expand the genotypic spectrum of congenital NAD deficiency disorders and further implicate mutation of additional genes involved in de novo NAD synthesis as potential causes of complex birth defects.

中文翻译：

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NADSYN1中的双等位基因突变会导致多个器官缺陷，并扩大先天性NAD缺乏症的基因型谱。

在所有活产婴儿中，出生缺陷的发生率高达3％，是婴儿死亡的主要原因。在这里，我们介绍了来自四个无关家庭的五个个体，这些个体在NADSYN1中具有与疾病致因的双等位基因变体相似的表型，编码NAD合成酶1（烟酰胺腺嘌呤二核苷酸（NAD）从头合成途径的最终酶）。缺陷的范围从孤立的两个肾脏缺失到椎骨，心脏，四肢和肾脏的多种畸形，并且没有受影响的个体在出生后三个月内存活。NAD是许多细胞过程中必不可少的辅酶。先前已在具有影响心脏，肾脏，椎骨和四肢的多个先天性异常的个体中确定了从头合成NAD所需基因的双等位基因功能丧失突变。通过酵母互补和酶促测定相结合的NADSYN1错义变体的功能评估显示酶活性受损和NAD水平严重降低。因此，NADSYN1代表胚胎发生过程中NAD合成所需的另一个基因，并且NADSYN1具有双等位基因错义变体，可导致NAD缺乏依赖性畸形。我们的发现扩大了先天性NAD缺乏症的基因型谱，并进一步暗示了涉及从头NAD合成的其他基因突变，这是复杂的先天缺陷的潜在原因。NADSYN1代表胚胎发生过程中NAD合成所需的另一个基因，并且NADSYN1具有双等位基因错义变体，会导致NAD缺乏依赖性畸形。我们的发现扩大了先天性NAD缺乏症的基因型谱，并进一步暗示了涉及从头NAD合成的其他基因突变，这是复杂的先天缺陷的潜在原因。NADSYN1代表胚胎发生过程中NAD合成所需的另一个基因，并且NADSYN1具有双等位基因错义变体，会导致NAD缺乏依赖性畸形。我们的发现扩大了先天性NAD缺乏症的基因型谱，并进一步暗示了涉及从头NAD合成的其他基因突变，这是复杂的先天缺陷的潜在原因。