Biallelic mutations in NALCN: Expanding the genotypic and phenotypic spectra of IHPRF1

Abstract

Loss-of function mutations in NALCN on chromosome 13q, a sodium leak channel that maintains baseline neuronal excitability, cause infantile hypotonia with psychomotor retardation and characteristic faces 1 (IHPRF1, OMIM #615419). Here, we document two individuals with early onset hypotonia with poor feeding and intellectual disability who were compatible with a diagnosis of IHPRF1. The two patients had bi-allelic mutations in NALCN through two different genetic mechanisms: Patient 1 had bi-allelic splice site mutations, that is c.1267-2A>G, derived from heterozygous parents, while Patient 2 had a partial maternal uniparental isodisomy that harbored a frameshift mutation, that is c.2022_2023delAT, in chromosome 13 that was detected through a dedicated algorithm for homozygosity data mapping in whole exome sequencing. The delineation of the exact pattern of inheritance provided vital information regarding the risk of recurrence. In animal models with Nalcn mutations, two behavioral phenotypes, that are, postnatal dyspnea and sleep disturbance, have been reported. Our observations of the two patients with postnatal dyspnea and one patient with sleep disturbance support an association between these two behavioral phenotypes and NALCN mutations in humans. The routine use of a detection algorithm for homozygosity data mapping might improve the diagnostic yields of next-generation sequencing.

<p>A Homozygous Truncating Mutation in <em>NALCN</em> Causing IHPRF1: Detailed Clinical Manifestations and a Review of Literature</p>

“…Cardiovascular malformation, however, is seldom associated with IHPRF1. To the best of our knowledge, other than the current case, there is only one other reported individual diagnosed with ASD, 27 and there is no previous report of TR in IHPRF1 patients.…”

Clinical and genetic characteristics of the syndrome of contractures of the limbs and face, hypothony and psychomotor retardation (OMIM: 616 266), caused by mutations in the NALCN gene

“…Наличие мутаций в гетерозиготном состоянии в гене приводят к возникновению синдрома ККЛГЗР, который характеризуется сочетанием диффузной мышечной гипотонии с задержкой психомоторного развития и дистального артрогрипоза, в то время как гомозиготные и компаунд-гетерозиготные мутации обнаружены у больных с сочетанием мышечной гипотонии, задержкой психомоторного развития и характерных лицевых дизморфий, но не сопровождающихся артрогрипозом (ОMIM:615 419). По мнению ряда авторов особенности клинических проявлений этих 2 нозологических форм, являющихся аллельными вариантами, объясняются различным эффектом мутаций в гене NALCN [11]. Показано, что белковый продукт гена NALC имеет 4 гомологичных домена, состоящих из 6 трансмембранных спиралей (S1-S6), отделенных друг от друга 3 цитоплазматическими петлями [4].…”

“…Такая эволюционная консервативность показывает важность белка NALCN для регуляции деятельности клетки [11], а следовательно, нарушение этого белка может быть патогенетическим механизмом других заболеваний как моногенной, так и мультифакторной природы [16].…”

Epilepsy-associated Mutations in the Calcium-sensing Receptor Disrupt the Regulation of NALCN Sodium-leak Channel by Extracellular Calcium in Neurons

“…NALCN also associates with a smaller subunit NLF-1 (FAM155A) (Kschonsak et al, 2020; Xie et al, 2013). Mutations in humans and other animals in the complex result in developmental delay, hypotonia, epilepsy, lack of speech development, severe intellectual disability, breathing deficiency, disrupted circadian rhythm, altered sensitivity to anesthetics and premature death (Al-Sayed et al, 2013; Angius et al, 2018; Aoyagi et al, 2015; Bramswig et al, 2018; Campbell et al, 2018; Chong et al, 2015; Humphrey et al, 2007; Jospin et al, 2007; Koroglu et al, 2013; Kuptanon et al, 2019; Lear et al, 2013; Nash et al, 2002; Obeid et al, 2018; Perez et al, 2016; Pierce-Shimomura et al, 2008; Ren, 2011; Shamseldin et al, 2016; Stray-Pedersen et al, 2016; Takenouchi et al, 2018; Valkanas et al, 2016; Wie et al, 2020; Yeh et al, 2008).…”