NALCN encodes a sodium ion leak channel expressed in the nervous system that conducts a persistent influx of sodium ions to facilitate action potential formation. Homozygous or compound heterozygous loss of function variants in NALCN cause infantile hypotonia with psychomotor retardation and characteristic facies‐1 (IHPRF1; OMIM 615419). Through exome and Sanger sequencing, we found two siblings of Afro‐Caribbean ancestry who are homozygous for a known NALCN pathogenic variant, p.Arg735Ter, leading to failure to thrive, severe hypotonia, and dolichocephaly. The older sibling died suddenly without a known etiology after evaluation but before molecular diagnosis. An international collaboration originating from a resource limited Caribbean island facilitated molecular diagnosis. Due to its small population, geographical isolation, and low socioeconomic status, the island lacks many specialty medical services, including clinical genetics. Descriptions of genetic disorders affecting individuals of Afro‐Caribbean ancestry are rarely reported in the medical literature. Diagnosis of IHPRF1 is important, as individuals with biallelic pathogenic NALCN variants are severely affected and potentially are at risk for cardiorespiratory arrest. Additionally, knowing the pathogenic variants allows the possibility of prenatal or preimplantation genetic diagnosis.

中文翻译：

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在两个非洲裔加勒比兄弟姐妹中出现低渗和多头畸形的纯合的截短的NALCN变体。

NALCN编码在神经系统中表达的钠离子泄漏通道，该通道传导钠离子的持续流入，以促进动作电位的形成。NALCN中纯合子或复合杂合子功能变异的丧失会导致小儿肌张力低下，并伴有精神运动发育迟缓和特征性相-1（IHPRF1； OMIM 615419）。通过外显子组和Sanger测序，我们发现了非洲加勒比血统的两个兄弟姐妹，他们是已知NALCN的纯合子致病性变体，p.Arg735Ter，导致无法正常成长，严重的肌张力低下和多头畸形。在评估后但在进行分子诊断之前，年长的兄弟姐妹突然死亡，没有已知病因。源自资源有限的加勒比海岛屿的国际合作促进了分子诊断。由于人口少，地域偏僻，社会经济地位低，该岛缺乏许多专业医疗服务，包括临床遗传学。在医学文献中很少报道影响非洲加勒比血统个体的遗传疾病。IHPRF1的诊断很重要，因为患有双等位基因致病性NALCN的个体这些变异会受到严重影响，并可能有心肺骤停的危险。另外，了解致病变体可以进行产前或植入前遗传学诊断。