ClinGen Dosage Sensitivity Curation Page

15q13.3 recurrent region (BP4-BP5) (includes CHRNA7)

  • Curation Status: Complete
  • id: ISCA-37411
  • Date last evaluated: 2018-04-27
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 3
  • ClinGen Triplosensitivity Score: 1


Location Information

Select assembly: (NC_000015.9) ()
Evidence for haploinsufficiency phenotype
PubMed ID Description
18278044 Sharp et al. (2008) reported six unrelated probands (along with three affected carrier family members; total of nine patients) with deletion of the 15q13.3 (BP4-BP5) region. Clinical findings in common across patients included developmental delays, intellectual disability, and dysmorphic features. Some patients also had a history of seizures, hypotonia, or abnormal EEG. Inheritance was known for 4 individuals: two probands had de novo deletions and two inherited the deletion from an affected parent. Both mothers and a sibling that carried the deletion were clinically affected. No deletions were identified in the 960 controls screened (p=0.005).
19289393 Ben-Shachar et al. (2009) reported clinical findings of 12 families (14 children and six parents; total of 20 individuals) with deletion of the 15q13.3 region identified through routine array testing; 11 families with 15q13.3 (BP4-BP5) deletion and one with a BP3-BP5 deletion. Phenotypes in the children included developmental delay, intellectual disability, ASD, speech delay, aggressiveness, ADHD, and other behavioral problems. Facial appearances ranged from normal to moderately dysmorphic. Epilepsy was observed in only one of 14 children and in none of the parents. Inheritance was known for seven probands: one deletion was de novo and six were inherited. Two fathers with the deletion had learning disabilities and bipolar disorder; the other four parents with the deletion were clinically unaffected.
19136953 Helbig et al. (2009) identified 11 unrelated probands with 15q13.3 (BP4-BP5) deletions and one patient with a BP3-BP5 deletion from a combined cohort with idiopathic generalized epilepsy (GE). Comparison of clinical findings to those reported originally for the 15q13.3 microdeletion syndrome showed notable differences: only three probands had intellectual disability, 9 did not have dysmorphic features or intellectual disability. Inheritance was known for 5 individuals: one deletion was de novo and four were inherited. One carrier parent was described as having a panic disorder while the other carrier parents were clinically unaffected. Siblings that carried the deletion had epilepsy or intellectual disability. The frequency of 15q13.3 deletions was compared to ancestrally matched controls; altogether, 15q13.3 deletions were observed in 12/1223 cases and in 0/2669 controls (p=5.32E-8). The authors suggest there is ?extensive variability in the phenotypic manifestation associated with 15q13.3 deletion?

Haploinsufficiency phenotype comments:

Deletion of the 15q13.3 (BP4-BP5) region* has been reported in over 200 individuals in the medical literature (Reviews: GeneReviews, PMID 21290787; Gillentine and Schaaf PMID 26095975). Clinical findings associated with BP4-BP5 deletion are variable and may include intellectual disability/developmental delay, epilepsy/seizures, autism spectrum disorder, speech delay, abnormal behaviors, mood disorders/schizophrenia, and additional variable findings. Incomplete penetrance has been reported; approximately 20% of cases are de novo. 15q13.3 (BP4-BP5) deletions have also been observed in individuals from the general population (controls) and in unaffected relatives. *The 15q proximal 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 (BP) within the 15q13.3 (BP4-BP5; includes CHRNA7) region. Note that genes used as landmarks are not necessarily causative of the phenotype(s) associated with the region. Additional relevant 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 (BP4-BP5) region were observed in 65/29,085 cases versus 0/19,584 controls (p= 2.85E-15, LR=INF (17 to INF)), demonstrating enrichment in the clinical population. See also Kaminsky et al., PMID: 21844811, p=1.44E-10; Uddin et al., 2018 PMID 29395074, p<1.3E-29) Additional cases PMID 26963284 Ziats et al. (2016) conducted a systematic neurobehavioral assessment of 15 unrelated patients with 15q13.3 (BP4-BP5) deletions and three patients (two siblings and one unrelated patient) with deletions extending from BP3 to BP5 (total of 14 males and 4 females). Cognitive/behavioral phenotypes across this cohort included intellectual disability/developmental delay, ASD, hyperactivity, attention problems, and additional behavioral phenotypes. Other clinical findings in common included epilepsy/seizures and hypotonia. Five of 18 patients (28%) had a second unrelated CNV, interpreted as VUS. Inheritance was known in six cases: one deletion was de novo and five deletions were maternally inherited; four were inherited from a mother who had a history of neuropsychiatric disease, and one was inherited from a phenotypically normal mother (not formally tested). PMID: 26997942 Hassfurther et al. (2016) described 6 new patients with deletion of the 15q13.3 (BP4-BP5) region (4 related and 2 unrelated, Patients 1-5 and 7) and one patient with 15q13.3 (BP3 to BP5) deletion (Patient 6). Clinical findings in common across patients included intellectual deficits, developmental delay, language problems, and ADHD. The inheritance was unknown in all cases. The authors conclude, ?the clinical phenotype of the microdeletion 15q13.3 is of multifactorial origin.? See also PMIDs: 18805830, 19372089, 20236110, 22083728, 25077648.

  • Triplosensitivity score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity
Evidence for gain of function phenotype
PubMed ID Description
19372089 van Bon et al. (2009) reported clinical findings of three unrelated individuals with duplication of the 15q13.3 (BP4-BP5) region (cases 20-22) and one patient with a BP3-BP5 duplication (case 23). For case 23, an unrelated paternally inherited duplication was also identified. Clinical findings in at least two individuals included intellectual disability, behavioral problems, autism, hypotonia, obesity, recurrent ear infections and low set ears. One BP4-BP5 duplication was de novo, while inheritance was unknown for the other two. The BP3-BP5 duplication was inherited from an unaffected father. The authors state, ?To conclude whether this duplication is pathogenic is rather difficult with the limited number of patients in our cohort and the unknown inheritance in two of them.?
18805830 Miller et al. (2009) reported three unrelated individuals with 15q13.3 (BP4-BP5) duplications (Patients 6-8). Clinical findings in common across patients included: autism spectrum disorder, language delay, and intellectual disability. Two duplications were de novo and one was inherited from an unaffected mother.
26997942 Hassfurther et al. (2016) described a new patient (Patient 8) with a duplication involving the recurrent 15q13.3 (BP4-BP5) region with dysmorphic features (low-set ears, hypertelorism, strabismus, and hypotonia), delayed psychomotor development, intellectual deficits, language problems, behavioral problems, and ventricular and atrial septal defects. The duplication was inherited from a phenotypically normal father. A maternal uncle with epilepsy and malignant hyperthermia was noted.

Triplosensitivity phenotype comment:

Evidence supporting pathogenicity of 15q13.3 (BP4-BP5) region* duplication is currently limited at this time. Duplications of this region have been observed in association with variable clinical findings (Summarized by Gillentine and Schaaf, PMID 26095975). Although at least three probands with de novo duplications of 15q13.3 (BP4-BP5) have been reported, inheritance from unaffected parents has also been reported. Duplications of this region are also somewhat common in the general population. In addition, multiple studies comparing the relative prevalence of 15q13.3 (BP4-BP5) duplications in patients versus controls have failed to show enrichment of this duplication within the clinical population (reviewed below). Therefore the triplosensitivity score is 1. *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 (BP) within the 15q13.3 region (BP4-BP5; includes CHRNA7). Note that genes used as landmarks are not necessarily causative of the phenotype(s) associated with the region. Additional relevant 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 (BP4-BP5) region were observed in 28/29,085 cases versus 11/19,584 controls (p= 0.083, LR=1.71 (0.898 to 3.35)), demonstrating a lack of enrichment in the clinical population. See also Kaminsky et al., PMID: 21844811, p=0.083; Sahoo et al., PMID: 21792059, p=0.6598. Sharp et al (PMID: 18278044) report finding this duplication in one of 960 controls; Helbig et al. (PMID: 19136953) reported duplication of this region in 3 controls. Review PMID: 26095975 Gillentine and Schaaf (2015) reviewed the literature and summarized clinical findings of a total of 18 patients with 15q13.3 (BP4-BP5) duplications. The phenotypic findings are summarized: cognitive deficits and ASD (n=7, 43.8%); ADHD or attention difficulties (n=5, 31.3%); language or speech impairment (n=5, 31.3%); seizures, epilepsy, and/or EEG abnormalities (n=3, 18.8%), mood disorders (n=3, 18.8%), and schizophrenia (n=1, 6.25%); and dysmorphic features (n=4, 25%). Of the 18 patients reported, inheritance was known in seven cases: five were de novo and two were inherited from a phenotypically normal parent. The authors concluded that phenotypes of affected patients (n=16) mirror those associated with CHRNA7 deletions and both larger and smaller duplications (Table 1, Figure 4). Reviewed PMIDs: 19372089, 20231187, 22118685, 18805830, 20888040, 22911887, 25655306. Other case reports PMID: 19289393 Ben-Shachar et al. (2009) detected four cases of duplication of the BP4-BP5 region identified through routine array testing. Clinical descriptions and inheritance information were not provided. The authors state, ?it is not clear at present whether dupications in this region are benign or may cause phenotypic abnormalities? PMID: 20506139 Szafranski et al. (2010) reported four individuals with the BP4-BP5 duplication but did not provide clinical descriptions. Two were inherited and two had unknown inheritance. They concluded that the clinical significance was uncertain.