ClinGen Dosage Sensitivity Curation Page

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

  • Curation Status: Complete
  • id: ISCA-46295
  • Date last evaluated: 2018-05-10
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 3
  • ClinGen Triplosensitivity Score: Triplosensitivity unlikely


Location Information

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Evidence for haploinsufficiency 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.

Haploinsufficiency phenotype comments:

Deletion of *15q13.3 between D-CHRNA7 to BP5 has been associated with a broad spectrum of clinical phenotypes, including: cognitive deficits, seizures and/or EEG abnormalities, autism, ADHD, mood disorders, schizophrenia, and variable additional findings. Incomplete penetrance has been reported. This deletion is enriched in the clinical population. Please see the linked reviews for further evidence relating to the 15q13.3 (BP4-BP5) recurrent deletion/duplication and genes CHRNA7 and OTUD7A. *The 15q13.3 region contains a cluster of low copy repeats that mediate recurrent copy number changes through non-allelic homologous recombination. This review refers to deletions involving recurrent breakpoints within the 15q13.3 region (D-CHRNA7 to BP5; includes CHRNA7 and OTUD7A). Note that genes used as landmarks are not necessarily causative of the phenotype(s) associated with the region. Deletions of this region include at least the proximal (5 prime) portion of CHRNA7 and the first exon of the OTUD7A gene (longer isoform, NM_130901.2). Additional literature is summarized below: Case-control studies PMID: 25217958 Coe et al. (2014): In a large-scale case-control comparison study of the relative prevalence of copy number variants in children with ID/DD, MCA, and other developmental phenotypes compared to controls, deletions of the recurrent 15q13.3 (D-CHRNA7 to BP5; includes CHRNA7) region were observed in 83/29,085 cases versus 0/19,584 controls (p= 2.64E-19, LR=Inf (22.2 - Inf)), demonstrating an enrichment in the clinical population. Other case reports PMID: 22031302 Mikhail et al. (2011) identified an ~537 kb heterozygous deletion at 15q13.3 that spans the entire CHRNA7 gene (and OTUD7A) with breakpoints at genomic positions 29,759,738 and 30,297,359 basepairs (hg18). The deletion was found in a 4 year old girl with limited speech, learning disability, and autistic features. Physically she has mild hypertelorism, upslanted palpebral fissures, and slightly diminished tone. Parents were not available for testing. PMID: 21990074 Liao et al. (2011) identified an ~410 kb HOMOZYGOUS deletion at 15q13.3 (chr15:29816893-30226405, hg18) in a 6-year-old girl with significant global developmental delay (nonambulatory and nonverbal), severe hypotonia, cortical visual impairment, staring spell seizures, and abnormal EEG. This homozygous deletion is predicted to remove the first 3 exons of CHRNA7 (the deletion does not contain any other genes). The mother and father each carry a heterozygous deletion of this region (by FISH). Both parents were in good health except the father had learning disability and the mother had bronchial asthma.

  • Triplosensitivity score: Triplosensitivity unlikely
  • Strength of Evidence (disclaimer): Triplosensitivity unlikely
Evidence for gain of function 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.

Triplosensitivity phenotype comment:

To date, the published evidence to suggest triplosensitivity of the *15q13.3 (D-CHRNA7 to BP5) region duplication is lacking. Duplications of this region are common in the general population and have an estimated prevalence of 1:174-186 individuals suggesting this duplication may represent a polymorphism. Given the frequency of these duplications in the general population and the lack of supportive evidence for pathogenicity, triplosensitivity of this region is considered unlikely. Please see the linked regions for further evidence relating to the 15q13.3 (BP4-BP5) recurrent deletion/duplication and genes CHRNA7 and OTUD7A. *The 15q13.3 region contains a cluster of low copy repeats that mediate recurrent copy number changes through non-allelic homologous recombination. This review refers to duplications involving recurrent breakpoints within the 15q13.3 region (D-CHRNA7 to BP5; includes CHRNA7 and OTUD7A). Note that genes used as landmarks are not necessarily causative of the phenotype(s) associated with the region. Duplications of this region include at least the proximal (5 prime) portion of CHRNA7 and the first exon of the OTUD7A gene (longer isoform, NM_130901.2). Additional literature is summarized below: Case-control studies PMID: 25217958 Coe et al. (2014): In a large-scale case-control comparison study of the relative prevalence of copy number variants in children with ID/DD, MCA, and other developmental phenotypes compared to controls, duplications of the recurrent 15q13.3 (D-CHRNA7 to BP5; includes CHRNA7 and OTUD7A) region were observed in 202/29,085 cases versus 139/19,584 controls (p= 0.576, LR=0.985 (0.812-1.)), demonstrating a lack of enrichment in the clinical population. Reviews PMID: 26095975 Gillentine and Schaaf (2015) review the literature and summarize a total of 67 patients reported with duplications involving the 15q13.3 region (D-CHRNA7 to BP5). The inheritance is unknown in 53 of the 67 (79.1%) patients reported (Figures 2 & 3). For the cases with known inheritance: none were de novo, eight were inherited from a phenotypically normal parent, two cases were inherited from an affected father (14.3%) and four were inherited from an affected mother (28.6%). The authors state that affected patients (n=60, 89.6%) had multiple clinical features, however, none of these features occurred in >33% of individuals (Table 1, Figure 4). The most frequent phenotypes were cognitive deficits and schizophrenia (n=17, 28.3). A normal phenotype was reported in 7/67 (10.4%) patients, all of which were carrier parents. PMID: 27853923 Gillentine et al (2017) sought to define the cognitive and behavioral phenotype of individuals with CHRNA7 duplications. Of 18 total duplications within 15q13.3, 16/18 patients had duplications mediated by D-CHRNA7 to BP5. All cases were inherited, with n=9 paternal and n=9 maternal. Of note, five patients had a second CNV outside of the 15q13.3 region, including one patient with a 22q11.2 deletion and 4 reported CNVs of uncertain significance. 65% of the cases were inherited from a parent with self- or family-reported neuropsychiatric issues such as mood disorders, learning disabilities, intellectual disability, ADHD, and schizophrenia. The remaining 35% of cases were inherited from unaffected parents; in addition, one proband had a carrier sibling who was unaffected. Therefore, these families also demonstrate incomplete penetrance and variable expressivity as seen in other studies. Other case reports PMID: 20506139 Szafanski et al (2010) reported five classes of the recurrent 15q13.3 (D-CHRNA7 to BP5) duplication in 55 out of 8832 individuals who had clinical microarray testing for various reasons. The clinical presentations include developmental delay, autism, ADHD, and psychiatric illness, but were not significantly different from the clinical findings for all patients tested clinically. All cases with parental data were inherited and many had other CNVs present as well.