Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity

Kurolap, Alina; Kreuder, Florian; Gonzaga‐Jauregui, Claudia; Duvdevani, Morasha Plesser; Harel, Tamar; Tammer, Luna; Xin, Baozhong; Bakhtiari, Somayeh; Rice, James Mahmud; Eyk, Clare L. van; Gécz, Jozef; Mah, Jean K.; Atkinson, Derek; Cope, Heidi; Sullivan, Jennifer; Douek, Alon M.; Colquhoun, Daniel; Henry, Jason; Wlodkowic, Donald; Parman, Yeşim; Candayan, Ayşe; Kocasoy-Orhan, Elif; Ilivitzki, Anat; Soudry, Shiri; Leibu, Rina; Glaser, Fabian; Sency, Valerie; Ast, Gil; Shashi, Vandana; Fahey, Michael; Battaloğlu, Esra; Jordanova, Albena; Meiner, Vardiella; Innes, A. Micheil; Wang, Heng; Elpeleg, Orly; Kruer, Michael C.; Kaslin, Jan; Feldman, Hagit Baris

doi:10.1016/j.ajhg.2022.01.004

Cited by 13 publications

(20 citation statements)

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“… Genetic findings in the patient (a), schematic representation of the NRCAM protein domains showing the location and type of the variant in this study (bolded) compared to the previously reported variants(Kurolap et al, 2022 ) (b) schematic representation of the detected ROH regions in this patient (c) …”

Section: Resultsmentioning

confidence: 85%

“…Therefore, we considered NRCAM deficiency as the cause of the observed phenotype in this patient. However, it is not clear if the missense variant in the TANC1 gene is only a benign rare polymorphism or has a synergistic or modifying effect on patient's symptoms (Douglas et al, 2009 ; Kurolap et al, 2022 ; Morelli et al, 2017 ).…”

Section: Resultsmentioning

confidence: 99%

“…NRCAM , along with L1CAM , CHL1 , and NFASC , belongs to the L1 subgroup of immunoglobin (Ig)‐CAMs that are highly expressed in the central nervous system. These proteins play essential roles in neural development by contributing to myelination, differentiation, proliferation, and migration, as well as synapsis formation, axonal growth, and guidance (Kurolap et al, 2022 ; Sakurai, 2012 ). The neuronal cell adhesion molecule, NRCAM, has overlapping functions with other L1‐IgCAMs.…”

Section: Introductionmentioning

confidence: 99%

“…This protein contains an N‐terminal signal peptide, six immunoglobin (Ig)‐like domains, five fibronectin III repeats, a transmembrane domain, and a C‐terminal cytoplasmic domain (Liang et al, 2020 ). The Ig‐like and Fn‐III domains at the extracellular region play critical roles in mediating the interaction between cells and adhesion signaling (Kurolap et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

“…Previous research has linked NRCAM variants to neuropsychiatric disorders such as autism, schizophrenia, drug addiction, and also to tumor progression (Liang et al, 2020 ; Sakurai, 2012 ). Recently, NRCAM bi‐allelic variants have been introduced to cause a neurodevelopmental syndrome of varying severity, mainly represented by developmental delay, intellectual disability, hypotonia, peripheral neuropathy, and/or spasticity (#MIM:619833) (Kurolap et al, 2022 ). To our knowledge, no other affected patients carrying NRCAM mutations have been reported later.…”

Section: Introductionmentioning

confidence: 99%

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Bi‐allelic loss of function variant in the NRCAM gene is associated with motor‐predominant axonal polyneuropathy; the second report

Elahi

Soveyzi

Nafissi

et al. 2023

Molec Gen & Gen Med

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Background The role of biallelic variants in the NRCAM gene underlying a neurodevelopmental disorder has been defined recently. The phenotype is mainly recognized by varying severity of global developmental delay/intellectual disability, hypotonia, spasticity, and peripheral neuropathy. Methods Here, we describe a patient with an initial diagnosis of motor‐predominant axonal polyneuropathy or a form of distal SMA. Whole‐exome sequencing (WES), in parallel with WES‐based CNV detection and assessment of homozygosity runs, was performed to identify this patient's possible genetic cause. Results Whole exome sequencing revealed a homozygous variant, c.73C > T (p.Gln25*), in the NRCAM gene, while the patient manifests a mild range of phenotypes compared to NRCAM ‐related disorder. He presented only motor‐predominant axonal polyneuropathy with no other signs of central nervous system involvement. Conclusions This study is the second report of an association between biallelic NRCAM gene variants and a Mendelian disorder. The obtained clinical data, together with the molecular findings in this patient, expands the clinical and molecular spectrum of NRCAM ‐related disorder and highlights its phenotypic complexity. Although patients with loss of function variants in this gene have previously presented severe clinical features, we show that type of the pathogenic variant does not necessarily determine the severity of this phenotype.

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Section: Resultsmentioning

confidence: 85%