ClinGen Dosage Sensitivity Curation Page

15q13.3 recurrent region (D-CHRNA7 to BP5) (includes CHRNA7 and OTUD7A)

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
19898479 Shinawi et al. (2009) describe 10 patients (two families and 4 unrelated individuals) with deletion of the 15q13.3 recurrent region (D-CHRNA7 to BP5). Clinical findings in common across patients include: mild to severe intellectual disability (5/10), global developmental delays (4/10), and seizures or abnormal EEG (4/10). Inheritance was known in 6 patients and all were maternally inherited. All carriers were affected.
20236110 Masurel-Paulet et al. (2010) describe three unrelated patients and parents (family 14-16) with deletion of the 15q13.3 recurrent region (D-CHRNA7 to BP5). Clinical findings in common across patients include: developmental delay and intellectual disability, language disabilities, and mildly dysmorphic features. Inheritance was known in all cases: one was paternal (patient 14), one was maternal (patient 16) and one was de novo (patient 15). The carrier parents were noted to have normal intelligence.
22775350 Hoppman-Chaney et al (2012) report 9 probands with heterozygous deletions of the recurrent 15q13.3 (D-CHRNA7 to BP5) region who had clinical features consistent with the 2 Mb 15q13.3 (BP4-BP5) microdeletion syndrome. Testing of two extended families showed that carrier parents, siblings, and other relatives had developmental delays and/or psychiatric conditions as well, with the exception of one infant sibling. Another 9 month old proband who was tested due to mild hypertelorism and chronic otitis media reportedly had normal development. Inheritance was known in three probands: one deletion was de novo and in two probands the deletion was inherited (one maternally and one paternally) from parents with psychiatric illness or learning problems. One additional proband had a homozygous deletion and was more severely affected.

Evidence for Triplosenstive Phenotype

Evidence for triplosensitivity phenotype
PubMed ID Description
26968334 Zhou et al. (2016) analyzed microarray data of 136 individuals with a diagnosis of childhood-onset schizophrenia and 135 of their apparently healthy siblings in an effort to identify new schizophrenia-associated copy number variants. This study described two unrelated individuals (Probands 1 and 2, Figure 1) with focal duplications of CHRNA7. These individuals had clinical features that included visual and auditory hallucinations, sleeping problems, and social impairment. Both duplications were paternally inherited. The father of proband 1 did not have a clinical diagnosis of schizophrenia but had a history of transient hallucinations and poor memory. Proband 1 had two siblings with the duplication and both had a neurodevelopmental disorder. The father of proband 2 had a clinical diagnosis of bipolar disorder and a history of alcohol abuse. Proband 2 also has a sibling that is a duplication carrier and was diagnosed with ADHD. There were no other duplication carriers identified in the healthy sibling group. The authors suggest that the duplication identified in their cohort is incompletely penetrant because they also identified the duplication in healthy siblings; however, these individuals had non-psychotic neurodevelopmental disorders that were previously associated with duplications of CHRNA7. They also suggest this duplication is variably expressive due to that fact that both fathers had neurodevelopmental disorders other than schizophrenia. The patient population in this study was compared against other clinical populations (AOS, ASD, ADHD, and ID) and their controls. The prevalence of CHRNA7 duplications in the general population was not discussed.
22420048 Williams et al (2012) report an association between duplication of the 15q13.3 (D-CHRNA7 to BP5) recurrent region and ADHD. Duplications were inherited in all cases with parental data. The authors conclude that these duplications are neither necessary nor sufficient to cause ADHD.

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.