ClinGen Dosage Sensitivity Curation Page

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

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function 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?

Evidence for Triplosenstive Phenotype

Evidence for triplosensitivity 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.

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.