Case Report: A de novo Variant in NALCN Associated With CLIFAHDD Syndrome in a Chinese Infant

Abstract

BackgroundThe NALCN encodes a sodium ion leak channel that regulates nerve-resting conductance and excitability. NALCN variants are associated with two neurodevelopmental disorders, one is CLIFAHDD (autosomal dominant congenital contractures of the limbs and face, hypotonia, and developmental delay, OMIM #616266) and another is IHPRF (infantile hypotonia with psychomotor retardation, and characteristic facies 1, OMIM #615419).Case PresentationIn the current study, a Chinese infant that manifested abnormal facial features, adducted thumbs, and neurodevelopmental retardation was diagnosed with CLIFAHDD syndrome. A trio-based whole-exome sequencing revealed that the infant harbored a de novo variant of the NALCN gene (c.4300A>G, p.I1434V).ConclusionsOur findings further enriched the variant spectrum of the NALCN gene and may expand the clinical range of NALCN-related disorders.

Clinical details of individuals with Rauch–Steindl syndrome due to NSD2 truncating variants

“…The diagram shows the structure of NSD2 . Previously reported NSD2 variants are shown in the NSD2 schematic (Barrie et al., 2019; Boczek et al., 2018; Derar et al., 2019; Hu et al., 2020; Jiang et al., 2019; Lozier et al., 2018; Yang et al., 2023; Zanoni et al., 2021). The novel variants of individual 1 and the recurrent variants of individual 2 in this study are boxed.…”

“…NSD2, a SET domain histone methyltransferase responsible for the methylation of H3K36, is expressed widely across many cells and tissues, and participates in various biological processes, including early development, cytokine signaling, the DNA damage response, and class switch recombination. (Yang et al., 2023; Zanoni et al., 2021). Loss‐of‐function variants in NSD2 may potentially influence cellular senescence, energy production, cell cycle regulation, and epigenetic accuracy (Tanaka et al., 2020).…”

“…NSD2 , also known as WHSC1 , has been considered a critical gene in WHS, 4p16.3 deletion syndrome. Recently, it has been reported that individuals with pathological variants in NSD2 share common facial features lack the so‐called ‘Greek warrior's helmet’ features specific to WHS, and their physical complications only partially overlap with those of WHS and are recognized as RAUST (Barrie et al., 2019; Boczek et al., 2018; Derar et al., 2019; Hu et al., 2020; Jiang et al., 2019; Lozier et al., 2018; Yang et al., 2023; Zanoni et al., 2021; Table S1). A detailed clinical examination of two individuals with RAUST in the present study revealed that facial features were consistent with previously reported features of RAUST (Zanoni et al., 2021).…”

“…Loss‐of‐function variants in NSD2 may potentially influence cellular senescence, energy production, cell cycle regulation, and epigenetic accuracy (Tanaka et al., 2020). To date, approximately 40 variants in NSD2 have been identified, and both missense and truncating variants are encompass various domains rather than being concentrated in specific domains (Barrie et al., 2019; Boczek et al., 2018; Derar et al., 2019; Hu et al., 2020; Jiang et al., 2019; Lozier et al., 2018; Yang et al., 2023; Zanoni et al., 2021; Figure 3). The novel nonsense and recurrent frameshift variant in this study are located near the PHD zinc finger domain and are stop codons that may result in NSD2 haploinsufficiency.…”

Case Report: New presentation of CLIFAHDD syndrome with a novel variant in the NALCN gene and a literature review

“…GPCRs modulate NALCN activity ( 11 ). IHPRF can be divided into two types: IHPRF1 (OMIM 615,419) is an autosomal recessive genetic disease caused by a biallelic variant of NALCN; and IHPRF2 (OMIM 616,801) is a disease caused by a biallelic variant of UNC80 ( 12 , 13 ). The case presented here was differentiated from IHPRF1.…”