17q12 Recurrent Duplication

Clinical characteristics.

In individuals with clinical manifestations the 17q12 recurrent duplication is characterized by intellectual abilities ranging from normal to severe disability and other variable clinical manifestations. Speech delay is common, and most affected individuals have some degree of gross motor delay. Seizures are present in 75%. Up to one third have eye or vision problems; cardiac and renal anomalies occur in rare cases. Other neurodevelopmental and psychiatric conditions reported in a subset of affected individuals are autism spectrum disorder, schizophrenia, and behavioral abnormalities (aggression and self-injury). The 17q12 recurrent duplication likely has reduced penetrance and variable expressivity since it is inherited in most instances from a parent who is often minimally affected or phenotypically normal.

Diagnosis/testing.

The 17q12 recurrent duplication is diagnosed by detection of a 1.4-Mb submicroscopic heterozygous duplication at the approximate position of chr17:34,815,072-36,192,492 Mb [GRCh37/hg19] in the reference genome. Individuals found to have this rare duplication were typically referred for testing because of intellectual disability and/or developmental delays, and occasionally because of multiple congenital anomalies.

Management.

Treatment of manifestations: Treatment should be tailored to the specific needs of the individual. Those with developmental delays, cognitive disability, and/or behavioral problems should be evaluated by a neurodevelopmental pediatrician or clinical psychologist/psychiatrist. Seizures should be managed by a neurologist using standard practice. Individuals with cardiac or renal abnormalities should be managed by the appropriate specialist.

Surveillance: Regular assessment of psychomotor development is recommended for all children with the 17q12 recurrent duplication as well as psychological evaluation in both affected children and adults.

Evaluation of relatives at risk: Presymptomatic diagnosis and treatment is warranted in at-risk relatives to identify as early as possible those who would benefit from close assessment/monitoring of developmental milestones in childhood or psychological assessment/intervention through adulthood.

Genetic counseling.

The 17q12 recurrent duplication is inherited in an autosomal dominant manner, with approximately 10% of duplications occurring de novo and approximately 90% inherited from a parent who is often minimally affected or phenotypically normal. Prenatal diagnosis for at-risk pregnancies requires prior identification of the duplication in an affected family member. Interpretation of results from prenatal testing is challenging given the inherent difficulty in accurately predicting the phenotype.

Suggestive Findings

The 17q12 recurrent duplication should be suspected in individuals with the following:

• Intellectual disability
• Developmental delays
• Multiple congenital anomalies
• Variable dysmorphic features
• Renal malformations

Of note, most individuals with the 17q12 recurrent duplication are identified by chromosomal microarray analysis (CMA) performed in the context of evaluation for developmental delay, intellectual disability, and/or autism spectrum disorder.

Establishing the Diagnosis

The diagnosis of the 17q12 recurrent duplication is established by detection of the 1.4-Mb heterozygous duplication at chromosome 17q12.

For this GeneReview, the 17q12 recurrent duplication is defined as the presence of a 1.4-Mb submicroscopic heterozygous duplication at the approximate position of chr17: 34,815,072-36,192,492 Mb [GRCh37/hg19] in the reference genome.

Note: The phenotype of significantly larger or smaller duplications or deletions within this region may be clinically distinct from the 17q12 recurrent duplication (see Genetically Related Disorders).

Although several genes of interest (e.g., ACACA, LHX1, HNF1B) are within the 1.4 Mb recurrent duplication, no single gene has been identified as causative of the associated phenotypes (see Molecular Genetics for genes of interest in the duplicated region).

Genomic testing methods that determine the copy number of sequences in DNA can include chromosomal microarray (CMA) or targeted deletion/duplication analysis.

Note: The 17q12 recurrent duplication is submicroscopic and cannot be identified by routine analysis of G-banded chromosomes or other conventional cytogenetic banding techniques.

• Chromosomal microarray (CMA) using oligonucleotide arrays or SNP arrays can detect the recurrent duplication in a proband. The ability to size the duplication depends on the type of microarray used and the density of probes in the 17q12 region.
  Note: (1) Most individuals with the 17q12 recurrent duplication are identified by CMA performed in the context of developmental delay, intellectual disability, and/or autism spectrum disorders. (2) Prior to 2008, many CMA platforms did not include coverage for this region and thus may not have detected this deletion.
• Targeted duplication analysis. FISH analysis, quantitative PCR (qPCR), multiplex ligation-dependent probe amplification (MLPA) or other targeted quantitative methods may be used to test relatives of a proband known to have the 17q12 recurrent duplication.
  Note: (1) Targeted duplication testing is not appropriate for an individual in whom the 17q12 recurrent duplication was not detected by CMA designed to target this region. (2) It is not possible to size the duplication routinely by use of targeted methods.

Evaluating at-risk relatives. FISH, qPCR, or other quantitative methods of targeted duplication analysis can be used to identify the 17q12 recurrent duplication in at-risk relatives of the proband. Testing of parental samples is important in determining recurrence risk (see Genetic Counseling).

Clinical Description

The 17q12 recurrent duplication was first reported in 2006 in a single individual with intellectual disability [Sharp et al 2006]. Since that initial description, at least 46 individuals with some phenotype data have been published [Sharp et al 2006, Mefford et al 2007, Mencarelli et al 2008, Nagamani et al 2010, Faguer et al 2011, Brandt et al 2012, Bierhals et al 2013, Girirajan et al 2013, Hardies et al 2013, Smigiel et al 2014, Mitchell et al 2015]. Individuals found to have this rare duplication were typically referred for testing because of intellectual disability and/or developmental delays, and occasionally because of multiple congenital anomalies. The 17q12 recurrent duplication likely also has reduced penetrance and variable expressivity since it is inherited in most instances from a parent with findings reported to be minimally abnormal or normal.

Developmental delay and intellectual disability (ID). Intellectual abilities range from normal to severe ID. The majority of affected individuals (30/34) are reported to have delays or intellectual disability. However, the true incidence may be lower given variable expressivity and the ascertainment bias that is present due to the fact that most individuals who are found to have the 17q12 duplication are referred because of developmental delays or ID. Speech delay is common (24/28). Most affected individuals (17/29) have some degree of gross motor delay.

Seizures are reported in at least 75% of affected individuals. MRI occasionally reveals abnormalities including focal cortical dysplasia, agenesis of the corpus callosum, periventricular leukomalacia, and possible schizencephaly.

Dysmorphic features. Most affected individuals have minor dysmorphisms, but there are no consistent features.

• Numerous dysmorphic features have been reported in one individual.
• Features reported in three or fewer individuals include trigonocephaly, plagiocephaly, low hairline, synophrys, thick eyebrows, long eyelashes, deeply set eyes, prominent ears, bulbous nose, thick lips, and short philtrum.
• Five individuals with slanted palpebral fissures (specifically 3 upslanted and 2 downslanted) have been described.

Eye or vision abnormalities including strabismus, astigmatism, amblyopia, cataract, coloboma, and microphthalmia occur in up to 43% of individuals.

Microcephaly is reported in approximately 50% of patients.

Other neurodevelopmental and psychiatric conditions reported in a subset of affected individuals are autism spectrum disorder, schizophrenia, and behavioral abnormalities (including aggression and self-injury and compulsive disorders).

Other anomalies. Though described in some individuals, other anomalies are not frequent.

• Cardiac. The most common reported congenital heart defect is a small ventricular septal defect.
• Renal abnormalities, present in approximately 25% of individuals, include horseshoe kidney, renal cysts, and hypoplastic kidneys.
• Tracheoesophageal fistula has been reported in three patients.

Penetrance

The penetrance of the 17q12 recurrent duplication has not been established. Although an estimated penetrance of approximately 21% has been proposed [Rosenfeld et al 2013], the majority of 17q12 recurrent duplications are inherited from a parent who is often minimally affected or phenotypically normal, making the true penetrance difficult to ascertain.

Prevalence

In four studies of apparently unaffected controls, the 17q12 recurrent duplication was present in 1/2443 individuals [International Schizophrenia Consortium 2008, Itsara et al 2009, Shaikh et al 2009, Moreno-De-Luca et al 2010]. In a population study of 101,655 individuals from Iceland, the prevalence was 1/2,675 [Stefansson et al 2014]

In two different studies of individuals with intellectual disability, developmental delay or autism, the 17q12 recurrent duplication was reported in 5/2,034 (0.25%) individuals [Mitchell et al 2015] and 21/15,749 (0.13%) [Moreno-De-Luca et al 2010]; however, the frequency is much lower when accounting for all samples submitted in a clinical laboratory setting (19/22,231, 0.085%) [Mitchell et al 2015].

In a cohort of individuals with schizophrenia, the 17q12 recurrent duplication was identified in 4/4,719 (0.08%) individuals [Szatkiewicz et al 2014].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with the 17q12 recurrent duplication, the following evaluations are recommended:

• General clinical examination
• Assessment by neurodevelopmental pediatrician and/or clinical psychologist/psychiatrist to determine extent of delays
• Evaluation by a neurologist if neurologic features are present or there is suspicion of seizures
• Ophthalmologic evaluation
• Echocardiogram
• Renal ultrasound examination
• Consultation with gastroenterologist and/or feeding team for GI concerns, suspected dysphagia, or feeding difficulties
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Treatment should be tailored to the specific needs of the individual. Those with developmental delays, cognitive disability, behavioral problems, or psychological phenotypes (autism spectrum disorder, schizophrenia) should be evaluated by a neurodevelopmental pediatrician or clinical psychologist/psychiatrist for treatment recommendations.

Seizures should be managed by a neurologist using standard practice.

Individuals with cardiac, ophthalmic, or renal abnormalities should be managed by the appropriate specialist.

Surveillance

Regular assessment of psychomotor development is recommended for all children with the 17q12 recurrent duplication. Referral to an early intervention program will likely be of considerable benefit.

Evaluation of Relatives at Risk

It is appropriate to employ genetic testing to evaluate the older and younger sibs of a proband previously found to have the 17q12 recurrent duplication in order to identify as early as possible those who would benefit from close assessment/monitoring of developmental milestones in childhood or psychological issues through adulthood.

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 www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions.