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Intellectual disability

Gene: NRCAM

Green List (high evidence)
NRCAM (neuronal cell adhesion molecule)
EnsemblGeneIds (GRCh38): ENSG00000091129
EnsemblGeneIds (GRCh37): ENSG00000091129
OMIM: 601581, Gene2Phenotype
NRCAM is in 4 panels

4 reviews

Arina Puzriakova (Genomics England Curator)

Green List (high evidence)

The rating of this gene has been updated to Green and the mode of inheritance set to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.
Created: 30 Jan 2023, 5:50 p.m. | Last Modified: 30 Jan 2023, 5:50 p.m.
Panel Version: 4.53
Created: 30 Jan 2023, 5:50 p.m.
Last Modified: 30 Jan 2023, 5:50 p.m.
Panel version: 4.53

Eleanor Williams (Genomics England Curator)

Removed the Q3_22_MOI tag as this is not a new gene that was added since the last sign off (although it was grey).
Created: 11 Oct 2022, 1:49 p.m. | Last Modified: 11 Oct 2022, 1:49 p.m.
Panel Version: 3.1742
Created: 11 Oct 2022, 1:49 p.m.
Last Modified: 11 Oct 2022, 1:49 p.m.
Panel version: 3.1742

Sarah Leigh (Genomics England Curator)

Green List (high evidence)

Associated with relevant phenotype in OMIM and as moderate Gen2Phen gene for NRCAM neurodevelopmental disorder with dysmorphic features, hypotonia and spasticity. At least 12 variants have been reported in PMID: 35108495 in 8 unrelated cases (table 1). Global developmental delay / intellectual disabilty was evident in 5/7 unrelated cases (individual 1 was not considered as they also had homozygous loss-of-function variant in CD55 (OMIM: 125240)(PMID: 35108495).
Created: 25 Aug 2022, 12:36 p.m. | Last Modified: 25 Aug 2022, 12:36 p.m.
Panel Version: 3.1687
Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Created: 25 Aug 2022, 11:53 a.m. | Last Modified: 25 Aug 2022, 11:53 a.m.
Panel Version: 3.1687
Created: 25 Aug 2022, 11:53 a.m.
Last Modified: 25 Aug 2022, 11:53 a.m.
Panel version: 3.1687

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Kurolap et al (2022 - PMID: 35108495) describe the phenotype of 10 individuals (from 8 families) with biallelic variants in NRCAM.

Features included tone abnormalities (hypotonia in 4/10, hypertonia/spasticity in 4/10), DD (8/10 - 7 families) and cognitive impairment (in 7/10 - 6 fam), neuropathy (4/10 - incl. 2 sibs without DD/ID). Other phenotypes incl. FTT (2/8), microcephaly (3/6), variable behavioral issues (3/5), abnormalities from the eyes/vision (6/8 - cataract in 2), abnormal hearing (3/7) or skeletal findings (8/9 - incl. scoliosis in 5). Nonspecific facial features were reported in 5/8.

Previous metabolic, genetic (incl. karyotype or CMA, FMR1, testing for Steinert disease or SMA) or other work-up (e.g. muscle biopsy) is reported for several subjects but was normal/non-diagnostic.

All were investigated by WES/WGS which revealed biallelic NRCAM variants. Sanger sequencing was used for confirmation and segregation analyses, with compatible results in several affected/unaffected sibs tested. There were no alternative explanations for the NDD phenotype with the exception of one subject with a mosaic functionally characterized LP KRAS variant suspected to contribute to his phenotype.

NRCAM encodes neuronal cell adhesion molecule (CAM). CAMs are membrane bound proteins with important role in tissue morphogenesis and maintenance. They mediate interactions between neighboring cells or cells and the extracellular matrix. The L1 subgroup of immunoglobulin CAMS - consisting of L1CAM, neurofascin, NRCAM, CHL1 - is the most abundant in the CNS with several critical functions in CNS development, among others in neural cell differentiation, axonal growth and guidance, myelination, synapse formation. Pathogenic L1CAM (XL) and NFASC variants (AR) are associated with NDD.

Different missense (N=7), stopgain/frameshift (N=3), a splice variant (NM_001037132.2:c.2647-2A>G) as well as a deep intronic one (c.230+824G>C / rs575851831). Variants occurred in different domains with a cluster (42%) in the fibronectin III domain.

Missense SNVs were ultrarare or not present in gnomAD, occurred in conserved residues, with several in silico predictions in favor of a deleterious effect. Structural modelling suggested that all substitutions occurred at residues exposed to solvent and possible abrogated interaction with other proteins.

There were no expression studies performed at the mRNA/protein level. The splice variant is predicted to cause ex22 skipping leading to frameshift. The deep intronic variant is predicted to disrupt a site for spl. regulator SC35 and may cause activation of a cryptic acceptor site with inclusion of a cryptic exon.

The zebrafish nrcama gene is the sole ortholog of human NRCAM, with another gene proposed as possible ortholog (nrcamb) mapping upon BLAST analysis to cntn1a. The authors performed CRISPR-Cas9 mutagenesis in zebrafish introducing a partial deletion of ex18 and 19. Mutant zebrafish were viable, displayed altered axonal projections and abnormal swimming behavior (increased movement in darkness).

Currently, there is no NRCAM-associated phenotype in OMIM/G2P/SysID. PanelApp Australia includes NRCAM in its ID panel with green rating.

Consider inclusion probably with green (>3 individuals/families/variants, segregation, gene in the L1-Ig CAM family causing NDD, zebrafish model) or amber rating (ID not a universal feature, variant effect not studied).
Sources: Literature
Created: 13 Mar 2022, 8:50 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Hypotonia; Hypertonia; Spasticity; Global developmental delay; Intellectual disability; Microcephaly; Behavioral abnormality; Neuropathy; Hearing abnormality; Abnormality of the eye; Abnormality of the skeletal system; Scoliosis; Abnormality of the face

Publications

Created: 13 Mar 2022, 8:50 p.m.

Panel version: 3.1518

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • NHS GMS
Phenotypes
  • Neurodevelopmental disorder with neuromuscular and skeletal abnormalities, OMIM:619833
OMIM
601581
Clinvar variants
Variants in NRCAM
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

30 Jan 2023, Gel status: 3

Removed Tag

Arina Puzriakova (Genomics England Curator)

Tag Q3_22_rating was removed from gene: NRCAM.

30 Jan 2023, Gel status: 3

Added New Source, Added New Source, Status Update

Arina Puzriakova (Genomics England Curator)

Source NHS GMS was added to NRCAM. Source Expert Review Green was added to NRCAM. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)

11 Oct 2022, Gel status: 2

Removed Tag

Eleanor Williams (Genomics England Curator)

Tag Q3_22_MOI was removed from gene: NRCAM.

25 Aug 2022, Gel status: 2

Added Tag, Added Tag

Sarah Leigh (Genomics England Curator)

Tag Q3_22_rating tag was added to gene: NRCAM. Tag Q3_22_MOI tag was added to gene: NRCAM.

25 Aug 2022, Gel status: 2

Entity classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

Gene: nrcam has been classified as Amber List (Moderate Evidence).

25 Aug 2022, Gel status: 0

Set Phenotypes

Sarah Leigh (Genomics England Curator)

Phenotypes for gene: NRCAM were changed from Hypotonia; Hypertonia; Spasticity; Global developmental delay; Intellectual disability; Microcephaly; Behavioral abnormality; Neuropathy; Hearing abnormality; Abnormality of the eye; Abnormality of the skeletal system; Scoliosis; Abnormality of the face to Neurodevelopmental disorder with neuromuscular and skeletal abnormalities, OMIM:619833

13 Mar 2022, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

gene: NRCAM was added gene: NRCAM was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: NRCAM was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NRCAM were set to 35108495 Phenotypes for gene: NRCAM were set to Hypotonia; Hypertonia; Spasticity; Global developmental delay; Intellectual disability; Microcephaly; Behavioral abnormality; Neuropathy; Hearing abnormality; Abnormality of the eye; Abnormality of the skeletal system; Scoliosis; Abnormality of the face Penetrance for gene: NRCAM were set to Complete Review for gene: NRCAM was set to GREEN