Clinical characteristics.

Individuals with the 15q13.3 recurrent deletion may have a wide range of clinical manifestations. The deletion itself may not lead to a clinically recognizable syndrome and a subset of persons with the recurrent deletion have no obvious clinical findings, implying that penetrance for the deletion is incomplete. A little over half of individuals diagnosed with this recurrent deletion have intellectual disability or developmental delay, mainly in the areas of speech acquisition and cognitive function. In the majority of individuals, cognitive impairment is mild. Other features reported in diagnosed individuals include epilepsy (in ~30%), mild hypotonia, and neuropsychiatric disorders (including autism spectrum disorder, attention-deficit/hyperactivity disorder, mood disorder, schizophrenia, and aggressive or self-injurious behavior). Congenital malformations are uncommon.

Diagnosis/testing.

The diagnosis of the 15q13.3 recurrent deletion is established in a proband by the presence of a heterozygous recurrent 2.0-Mb deletion at the approximate position of 30.5-32.5 Mb in the reference genome (chr15:30366247-32929476 [GRCh37/hg19]) that includes deletion of 1.5 Mb of unique sequence as well as an additional 500 kb or more of segmental duplications.

Management.

Treatment of manifestations: Epilepsy is treated with anti-seizure medication (ASM). The use of valproate has been successful in a number of affected individuals, while oxcarbazepine led to clinical worsening in one affected individual. However, a variety of ASMs may be used. Standard treatment for developmental delay / intellectual disability, neuropsychiatric disorders, congenital anomalies (cardiac and/or renal anomalies), refractive errors, strabismus, and chronic ear infections / glue ear.

Surveillance: Monitor developmental progress / education needs at each visit. Assessment for anxiety, attention, aggressive/self-injurious behavior, and new neurologic manifestations (such as seizures) at each visit. Annual audiology evaluation in infancy and childhood (or as clinically indicated). Ophthalmology evaluation per treating ophthalmologist(s).

Genetic counseling.

The 15q13.3 recurrent deletion is inherited in an autosomal dominant manner. Approximately 15% are de novo and approximately 85% are inherited. Offspring of an individual with this deletion have a 50% chance of inheriting the deletion. Although prenatal testing is technically feasible, it is not possible to reliably predict the phenotype based on the laboratory finding of the 15q13.3 recurrent deletion.

Suggestive Findings

The 15q13.3 recurrent deletion should be considered in individuals with the following clinical findings and family history.

Clinical features

• Intellectual disability
• Speech delay
• Seizures
• Autism
• Schizophrenia
• Behavioral findings including poor attention span, hyperactivity, mood disorder, and aggressive and/or impulsive behavior

Some affected individuals have combinations of these findings, such as intellectual disability and seizures.

Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of the 15q13.3 recurrent deletion is established in a proband by the presence of a heterozygous recurrent 2.0-Mb deletion at the approximate position of 30.5-32.5 Mb in the reference genome that includes deletion of 1.5 Mb of unique sequence as well as an additional 500 kb or more of segmental duplications (NCBI Genome Data Viewer) (see Table 1).

Note: (1) For the purposes of this chapter, the term "15q13.3 recurrent deletion" is defined as heterozygous and by the genomic coordinates provided in Table 1; it does not denote deletions outside of this region or biallelic deletions. (2) The phenotype of significantly larger or smaller heterozygous deletions within this region and of biallelic recurrent 15q13.3 deletions may be clinically distinct from the heterozygous recurrent 15q13.3 deletion (see Genetically Related Disorders).

Although several genes of interest (e.g., CHRNA7 and OTUD7A) are within the 2.0-Mb deletion, no single gene has been associated with the disease findings (see Molecular Genetics for genes of interest in the deleted region).

Genomic testing methods that determine the copy number of sequences can include chromosomal microarray (CMA) or targeted deletion analysis by fluorescence in situ hybridization (FISH), quantitative PCR, or multiplex ligation-dependent probe amplification (MLPA). Note: The 15q13.3 deletion cannot be identified by routine analysis of G-banded chromosomes or other conventional cytogenetic banding techniques.

• Chromosomal microarray (CMA) using oligonucleotide arrays or SNP genotyping arrays can detect the common deletion in a proband. The ability to size the deletion depends on the type of microarray used and the density of probes in the 15q13.3 region.
  Note: (1) Most individuals with the 15q13.3 recurrent deletion are identified by CMA performed in the context of developmental delay, intellectual disability, or autism spectrum disorders. (2) Prior to 2008 some CMA platforms did not include coverage for this region and thus may not have detected the deletion.
• Targeted deletion analysis. FISH analysis, quantitative PCR, and MLPA may be used to test at-risk relatives of a proband known to have the 15q13.3 recurrent deletion.
  Note: (1) Targeted deletion testing by FISH, quantitative PCR, or MLPA is not appropriate for an individual in whom the deletion was not detected by CMA designed to target the 15q13.3 region. (2) It is not possible to size the deletion routinely by use of FISH, quantitative PCR, or MLPA.

Clinical Description

More than 200 individuals with an approximately 2.0-Mb heterozygous recurrent deletion at 15q13.3 have been reported [Lowther et al 2015, Pavone et al 2020]. The following description of the phenotypic features associated with this condition is based on these reports. Note: To date, no clinically significant differences have been reported between individuals with deletions BP3-BP5 or BP3-BP4 compared to those with BP4-BP5. However, this chapter focuses specifically on those with the BP4-BP5 deletion [Pavone et al 2020], as this recurrent deletion accounts for about 94% of deletions in this recurrent deletion region [Lowther et al 2015].

Intellectual disability and developmental delay. Accounting for ascertainment, intellectual disability or developmental delay has been observed in approximately 59% of individuals with the 15q13.3 recurrent deletion [Lowther et al 2015, Pavone et al 2020]. Developmental delays are mainly delays in speech acquisition and cognitive function rather than motor disability, although hypotonia can contribute to mild motor delays (see Hypotonia). In the majority of individuals, cognitive impairment is mild. However, a subset of individuals with moderate-to-severe disability have been reported [Ben-Shachar et al 2009, van Bon et al 2009, Lowther et al 2015]. In a small study of 18 individuals with 15q13.3 deletions (15 with the recurrent BP4-BP5 deletion and 3 others with larger deletions that included BP3-BP5) who underwent comprehensive IQ assessment, the average verbal and nonverbal subcomponents of the IQ test were 64.3 and 60.1, respectively [Ziats et al 2016], suggesting no significant difference between verbal and nonverbal IQ scores in affected individuals.

Some individuals with the 15q13.3 recurrent deletion have no discernible clinical features, including developmental or cognitive delays. However, data on 23,838 adult "controls" (individuals who did not undergo genetic testing for an indication of developmental concerns or other clinical features) detected no 15q13.3 deletions [Lowther et al 2015]. Another study reporting on a population-based sample (n=101,655) identified 25 such recurrent deletions (0.025%) [Stefansson et al 2014].

Epilepsy. About 30% of individuals with the 15q13.3 recurrent deletion are diagnosed with epilepsy [Lowther et al 2015, Pavone et al 2020]. Children commonly present with absence seizures that start in childhood, but this could be accompanied by atypical features such as persistence into adolescence, early onset, absence status epilepticus, and treatment resistance. More rare generalized seizure types (such as myoclonic absence and atonic seizures in addition to focal with impaired awareness non-motor onset seizures) were also observed. EEG may show a mixture of generalized and focal findings. The presence of combined seizure types and EEG findings should be treated with caution, as some anti-seizure medications (ASMs) (i.e., specific sodium channel blockers such as oxcarbazepine) could potentially worsen seizures (see Management), although this requires further study. Valproate appeared effective, but more studies are needed to confirm the effectiveness of other ASMs and therapies [Whitney et al 2021].

Hypotonia. In general, hypotonia is mild and body muscular tone improves during childhood. Walking without support is often achieved between age 12 months and three years (average: 21.5 months). Hypotonia likely contributes to the delay in achievement of motor milestones reported in some individuals.

Neuroimaging. Brain MRI findings are not frequently observed or reported; they include rare reports of arachnoid cysts, cerebellar vermis hypoplasia, ventricular dilatation, corpus callosal agenesis, focal cortical dysplasia, and heterotopia. Other nonspecific findings such as mild prominence of extra cerebral spaces, focal volume loss, prominent cerebellar folia, and T₂ hyperintensities within the subcortical white matter have also been reported [Whitney et a 2021].

Neuropsychiatric disorders. Behavioral/psychiatric findings are present in about one third of individuals and mainly include autism spectrum disorder, attention-deficit/hyperactivity disorder (ADHD), mood disorder, self-mutilation, and aggressive and/or impulsive behavior [Lowther et al 2015].

In three studies, the 15q13.3 recurrent deletion was enriched in cohorts of individuals with schizophrenia compared to controls [International Schizophrenia Consortium 2008, Stefansson et al 2008, Lowther et al 2015]. Accounting for ascertainment bias, schizophrenia may be present in 11% of adult individuals with the 15q13.3 recurrent deletion [Lowther et al 2015].

Facial features. No specific dysmorphic features have been observed. If present, dysmorphic features are nonspecific [Pavone et al 2020].

Rare features. Severe congenital malformations are uncommon.

• Heart. Structural congenital cardiac malformations are seen in a low number of individuals (3%) [Lowther et al 2015]. Hypercholesterolemia has been occasionally reported.
• Ocular anomalies have been reported in 6% of individuals [Pavone et al 2020], most frequently strabismus and astigmatism.
• Hearing. In general, children and adults have normal hearing. However, temporary hearing loss due to recurrent ear infections in infancy may occur.
• Growth. Abnormalities in growth may occur (both undergrowth and overgrowth), although most children grow normally.

Other. It is unclear if the following represent rare findings of the 15q13.3 recurrent deletion or chance co-occurrences that are unrelated [van Bon et al 2009, Lowther et al 2015, Pavone et al 2020]:

• Gastrointestinal findings including gastrointestinal reflux disease, hiatal hernia, and diverticulosis
• Endocrine anomalies such as hypothyroidism and insulin-resistant diabetes
• Urogenital findings such as renal cyst, urethral stricture, and nephrolithiasis
• Placenta previa, present of 1.6% in probands (i.e., ≤5x the standard population estimates). However, further studies including the investigation of possible confounding risk factors are needed to confirm this finding [Lowther et al 2015].

Genotype-Phenotype Correlations

No phenotype-genotype correlations are known; the phenotypic findings in individuals with the 15q13.3 recurrent deletion range from normal to significantly impaired.

Penetrance

The penetrance of the 15q13.3 recurrent deletion is incomplete and highly variable. In total, 80.5% of reported individuals with the recurrent deletion have at least one of the following neurodevelopmental or neuropsychiatric diagnoses [Lowther et al 2015]:

• Developmental delay / intellectual disability
• Speech delays/impairment
• Epilepsy
• Autism spectrum disorder
• Schizophrenia
• Mood disorder
• ADHD

Nomenclature

Owing to the lack of a recognizable phenotype in persons with the 15q13.3 recurrent deletion, it has not been described eponymously. Although the 15q13.3 region includes other segmental duplication breakpoints [Makoff & Flomen 2007, Shinawi et al 2009], the 15q13.3 recurrent deletion specifically refers to deletion of the 2.0-Mb region at the approximate position of 30.5-32.5 Mb in the reference genome (NCBI Genome Data Viewer).

Prevalence

The prevalence of the 15q13.3 recurrent deletion in the general population is estimated at 1:5,500 [Gillentine et al 2018].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with the 15q13.3 recurrent deletion, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

Ideally, treatment is tailored to the specific needs of the individual. Because of the high incidence of neurodevelopmental disability, referral to a clinical psychologist for neuropsychological and/or developmental assessment for treatment recommendations is suggested.

Additional management in healthy adults who have the 15q13.3 recurrent deletion is not necessary, although their medical care providers may benefit from being alerted to the possible increased risk for late-onset manifestations (e.g., schizophrenia).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in Table 5 are recommended.

Agents/Circumstances to Avoid

About 11% of individuals with the 15q13.3 recurrent deletion develop schizophrenia. The use of cannabis has been reported as a risk factor for development of schizophrenia. Although no studies have been performed on the possible additional risk of the use of cannabis by persons with the 15q13.3 recurrent deletion, discouraging the use of cannabis may be considered.

It is unclear if oxcarbazepine should be avoided. In at least one affected individual with seizures, oxcarbazepine led to clinical worsening [Whitney et al 2021]. However, this is only a single case.

Evaluation of Relatives at Risk

Using genomic testing that will detect the 15q13.3 recurrent deletion found in the proband, it is appropriate to evaluate the older and younger sibs of a proband in order to identify as early as possible those who would benefit from close assessment/monitoring of developmental milestones in childhood.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

The 15q13.3 recurrent deletion is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• About 85% of individuals with a 15q13.3 recurrent deletion inherited the genetic alteration from a parent. The parent with the 15q13.3 recurrent deletion may be phenotypically normal or have features associated with the 15q13.3 recurrent deletion.
• The 15q13.3 recurrent deletion occurs de novo in approximately 15% of probands.
• Genomic testing that will detect the 15q13.3 recurrent deletion present in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the 15q13.3 recurrent deletion identified in the proband is not identified in either confirmed biological parent, the following possibilities should be considered:
  • The proband has a de novo deletion.
  • The proband inherited a deletion from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.

Sibs of a proband. The risk to sibs of a proband depends on the genetic status of the parents:

• If one of the parents has the 15q13.3 recurrent deletion identified in the proband, the risk to each sib of inheriting the deletion is 50%. It is not possible to predict the phenotype in sibs who inherit a 15q13.3 recurrent deletion because the penetrance of the deletion is incomplete and clinical manifestations are highly variable; phenotypic findings in individuals with the 15q13.3 recurrent deletion range from normal to significantly impaired.
• If the 15q13.3 recurrent deletion identified in the proband cannot be detected in either of the parents, the chance of recurrence to sibs is low (<1%) but greater than that of the general population because of the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with the 15q13.3 recurrent deletion has a 50% chance of inheriting the deletion; it is not possible to predict the phenotype in offspring who inherit the deletion.

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent has the 15q13.3 recurrent deletion, the parent's family members may also have the deletion.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with the 15q13.3 recurrent deletion.

Prenatal Testing and Preimplantation Genetic Testing

Pregnancies known to be at increased risk for the 15q13.3 recurrent deletion. Once a 15q13.3 recurrent deletion has been identified in a family member, prenatal and preimplantation genetic testing are possible.

Pregnancies not known to be at increased risk for the 15q13.3 recurrent deletion. CMA performed in a pregnancy for other indications (e.g., advanced maternal age) may detect the 15q13.3 recurrent deletion.

Note: Regardless of whether a pregnancy is known or not known to be at increased risk for the 15q13.3 recurrent deletion, the prenatal finding of a 15q13.3 recurrent deletion cannot be used to predict the phenotype (see Penetrance).

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

The proximal 15q region is characterized by a high density of low copy repeats [Bailey et al 2002, Makoff & Flomen 2007, Sharp et al 2008] and is therefore susceptible to several genomic rearrangements leading to partial aneuploidy. The breakpoints (BPs) of such rearrangements cluster in the low copy repeats. To date, six BPs have been characterized in the 15q11q14 region [Mignon-Ravix et al 2007]. The recurrent 2.0-Mb 15q13.3 deletion occurs between the breakpoints designated as BP4 and BP5 [Sharp et al 2008].

The 2.0-Mb deletion arises when the flanking low copy repeats are positioned in a direct orientation, most probably through a common inversion of the BP4-BP5 region, which generates a configuration predisposing to nonallelic homologous recombination [Sharp et al 2008].

Mechanism of disease causation. The 2.0-Mb microdeletion results in the loss of six known genes: MTMR15, TRPM1, MTMR10, KLF13, OTUD7A, and CHRNA7. How deletion of these genes results in the clinical findings of this condition is unknown; ongoing investigations may identify one or more genes as responsible for the phenotypic features.

Smaller 15q13.3 deletions overlapping only CHRNA7 and the first exon of OTUD7A have been found in individuals with developmental delay, intellectual disability, autism spectrum disorders, epilepsy, and schizophrenia (see Genetically Related Disorders), thus implicating one of those two genes as the likely cause of the neuropsychiatric manifestations of the 15q13.3 recurrent deletion. CHRNA7 encodes a synaptic ion channel protein mediating neuronal signal transmission [Taske et al 2002, Hong et al 2004, Leonard & Freedman 2006, Iwata et al 2007]. No individuals with a pathogenic loss-of-function variant in CHRNA7 have been reported to date. OTUD7A encodes a deubiquitinating enzyme localizing to dendritic spines in cortical neurons [Uddin et al 2018]. Loss-of-function pathogenic variants in OTUD7A have been reported in individuals with schizophrenia [Kozlova et al 2022]. A homozygous missense variant of OTUD7A was found in an individual with epileptic encephalopathy [Garret et al 2020], and biallelic loss of OTUD7A was reported in an individual with severe hypotonia, intellectual disability, and seizures [Suzuki et al 2021]. Neurologic phenotypes were also seen in an Otud7a knockout mouse [Garret et al 2020].

Revision History

• 17 November 2022 (ma) Comprehensive update posted live
• 23 July 2015 (me) Comprehensive update posted live
• 23 December 2010 (me) Review posted live
• 18 May 2010 (bvb) Original submission

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