ClinGen Dosage Sensitivity Curation Page

Gene Information

• id: ISCA-14852
• Date last evaluated: 2018-10-24
• Issue Type: ClinGen Gene Curation
• Gene type: protein-coding
• Entrez Gene: https://www.ncbi.nlm.nih.gov/gene/64478
• OMIM: https://omim.org/entry/608397

Location Information

• 8p23.2
• GRCh37/hg19 chr8: 2,792,875-4,852,328

Evidence for Loss Phenotypes

• Loss of function score: 1
• Strength of Evidence: Little evidence for dosage pathogenicity
• Haploinsufficiency Phenotype: Complex Neurodevelopmental Disorder

Evidence for loss of function phenotype

PubMed ID	Description
23375656	Girirajan et al. (2013) performed microarray analysis on a cohort of patients with autism spectrum disorders (simplex and multiplex) and controls. Intragenic losses in CSMD1 were observed in three individuals (13503.p1, 11225.p1, 12775.p1). Inheritance was not assessed as part of this study. Please note that subject 11225.p1 was also included in Levy et al.
21658582	Levy et al. (2011) performed microarray analysis on a cohort of patients with autism spectrum disorder (simplex and multiplex). Subject 11225.p1, who has a diagnosis of autism spectrum disorder, was observed to have a heterozygous loss in CSMD1 as a result of a de novo mutational event. Please note that subject 11225.p1 was also included in Girirajan et al.
22083728	Kirov et al. (2012) used microarray analysis to study a cohort of patients with schizophrenia. A 177kb intragenic deletion removing an exon of CSMD1 was observed in a male patient with a diagnosis of paranoid schizophrenia. This copy number loss was the result of a de novo mutational event.

• Loss of function phenotype comments: Papers not included in scoring because genes other than CSMD1 have altered dosage in the patient: Chien et al. (2010)(PMID: 20236125) describe a 10 year old patient with autism with a terminal deletion of 8p23.2-pter. This 2.4Mb copy number loss encompasses CSMD1 as well as 22 other RefSeq transcripts. Whether or not the 8p deletion was inherited or de novo in the proband was not reported. Nucaro et al. (2011) (PMID:21371014) report a 10 year old male with a complex chromosomal rearrangement of 8p and a clinical presentation of epilepsy, periventricular leukomalacia, intellectual disability, and autism. This patient's rearrangement includes a deletion of 8p23.2-term, including CSMD1, as well as duplication of 8p22-p23.1. The inheritance of these genomic variants was not reported. Naseer et al. (2015) (PMID 27766957) describe a family with multiple members affected by epilepsy and intellectual disability. A copy number loss of 8p23-21, including CSMD1, was observed in 4 of the 5 affected family members tested. Several copy number gains were observed in affected individuals and the family is noted to be consanguineous.

Evidence for Triplosenstive Phenotype

• Triplosensitivity score: 0
• Strength of Evidence: No evidence for dosage pathogenicity

• Triplosensitivity phenotype comment: Glancy et al. (2009) (PMID 18716609) reported a microduplication of 8p23.1-8p23.2 in a child diagnosed with autism and speech delay. The copy number gain was inherited from his mother, who was noted to have epilepsy and learning difficulty. The duplication included the 5' (centromeric) region of CSMD1, with the breakpoint for the duplication occurring mid-gene. The clinical significance of this partial-gene duplication is unclear and insufficient to assess triplosensitivity of CSMD1. Girirajan et al. (2013) (PMID: 23375656) performed microarray analysis on a cohort of patients with autism disorders (simplex and multiplex) and controls. An intragenic CSMD1 was observed in one patient (14152.p1). This partial gain was not considered informative regarding triplosensitivity.

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.