3q29 Recurrent Deletion

Clinical characteristics.

3q29 recurrent deletion is characterized by global developmental delay and/or intellectual disability, and commonly, speech delay, and increased risk for neuropsychiatric disorders (including autism spectrum disorder, anxiety disorder, psychosis, and/or schizophrenia). Other common findings are failure to thrive and feeding problems in infancy that persist into childhood, heart defects (especially patent ductus arteriosus), gastrointestinal disorders (including gastroesophageal reflux disease), and dental abnormalities. To date findings in fewer than 50 affected individuals have been reported.

Diagnosis/testing.

The diagnosis of the 3q29 recurrent deletion is established by detection of the 1.6-Mb heterozygous deletion by chromosomal microarray at the approximate position of chr3:195998129-197623129 in the reference genome (NCBI Build 38).

Management.

Treatment of manifestations: Early speech and language therapy to address speech delays; physical therapy as needed to address fine and gross motor delays; individualized education program (IEP) for school-age children; care by a child psychiatrist/psychologist as needed for neuropsychiatric disorders; feeding therapy and consideration of gastrostomy tube as needed; routine management of dental caries, congenital heart defects, recurrent ear infections.

Surveillance: Continued assessment of feeding and nutrition, developmental milestones, cognitive development, and possible neuropsychiatric manifestations.

Evaluation of relatives at risk: Parents and older and younger sibs of a proband should be tested for the 3q29 recurrent deletion to encourage close assessment/monitoring of developmental milestones (in children) and monitoring for neuropsychiatric manifestations (in children and adults).

Genetic counseling.

The 3q29 recurrent deletion is inherited in an autosomal dominant manner. Although most deletions are de novo, inherited deletions have been reported. If the 3q29 recurrent deletion identified in the proband is not identified in one of the parents, the risk to sibs is low (<1%) but greater than that of the general population because of the possibility of parental germline mosaicism for the deletion. Once the 3q29 recurrent deletion has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

The 3q29 recurrent deletion should be considered in individuals with the following clinical findings [Glassford et al 2016]:

• Global developmental delay or intellectual disability, including speech delay
• Autism spectrum disorder (ASD)
• Slight facial dysmorphology, including a long, narrow face; short philtrum; high nasal bridge; and large ears [Ballif et al 2008]
• Failure to thrive, failure to gain weight, and/or feeding problems in infancy that persist into childhood
• Heart defects, especially patent ductus arteriosus
• Gastrointestinal disorders, including gastroesophageal reflux disease (GERD)
• Dental abnormalities

Of note, most individuals with the 3q29 recurrent deletion are identified by chromosomal microarray (CMA) analysis performed in the context of evaluation for global developmental delay, intellectual disability, and/or ASD.

Establishing the Diagnosis

The diagnosis of the 3q29 recurrent deletion is established by detection of the 1.6-Mb heterozygous deletion at chromosome 3q29, typically by chromosomal microarray (CMA).

For this GeneReview, the 3q29 recurrent deletion is defined as the presence of a recurrent 1.6-Mb deletion at the approximate position of chr3:195998129-197623129 in the reference genome (NCBI Build 38).

This is a recurrent deletion, mediated by nonallelic homologous recombination (NAHR) between segmental duplications (or low-copy repeats) flanking the deletion region.

Note: The phenotype of significantly larger or smaller deletions within this region may be clinically distinct from the 3q29 recurrent deletion (see Genetically Related Disorders).

Although several genes of interest (e.g., DLG1, FBXO45, PAK2, RNF168) are within the 1.6-Mb recurrent deletion, no single gene in which pathogenic variants are causative has been identified (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. Note: The 3q29 recurrent 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 arrays can detect the recurrent deletion in a proband. The ability to size the deletion depends on the type of microarray used and the density of probes in the chr3:195998129-197623129 region.
  Note: (1) Most individuals with a 3q29 recurrent deletion are identified by CMA performed in the context of evaluation for developmental delay, intellectual disability, or autism spectrum disorder. (2) Prior to 2005 many CMA platforms did not include coverage for this region and thus may not have detected this deletion. This recurrent deletion was detected by early BAC arrays; at least 14 individuals with 3q29 deletion were identified with this technology [Ballif et al 2008].
• Targeted deletion 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 3q29 recurrent deletion.
  Note: (1) Targeted deletion testing is not appropriate for an individual in whom the 3q29 recurrent deletion was not detected by CMA designed to target chr3:195998129-197623129. (2) It is not possible to size the deletion routinely by use of targeted methods.

Evaluating at-risk relatives. FISH, qPCR, or other quantitative methods of targeted deletion analysis can be used to identify the 3q29 recurrent deletion in at-risk relatives of the proband. Testing parental samples is important in determining recurrence risk (see Genetic Counseling).

Clinical Description

Global developmental delay and/or intellectual disability (ID) are common to almost all individuals with the 3q29 recurrent deletion. Aside from this, clinical presentation can vary. Although some facial dysmorphology has been noted – including a long narrow face, short philtrum, high nasal bridge, and large ears [Ballif et al 2008] – the facial phenotype is subtle and not specific.

The summary below is based on the comprehensive review of all reported cases in Cox & Butler [2015] and the self-reported findings in 44 individuals from the 3q29 deletion registry [Glassford et al 2016].

The following clinical manifestations have been reported in more than one individual with the recurrent deletion.

In the first year of life

• Feeding problems (64%) and failure to gain weight (39%)
• Jaundice (34%)
• Hypotonia (34%) and hyporeflexia (7%)
• Respiratory distress (25%) (although this may have to do with normal respiratory disease due to RSV, parainfluenza, influenza, or rhinovirus, and may not be related to the deletion)
• Congenital heart defects including patent ductus arteriosus (12%), ventricular septal defect (5%), pulmonary valvar stenosis (5%)

Developmental delay. Specific data on developmental issues are limited. On average achievement of developmental milestones is delayed between six to twelve months (depending on the milestone). For example, walking is usually achieved at age 20 months (vs 12 months) and speaking single words at age 23 months (vs 12 months). Over time, children with the 3q29 deletion show a range of intellectual disability, with most having mild to moderate ID. Fewer than 5% have severe ID. Likewise, only one of 44 individuals reported to have the 3q29 deletion is completely nonverbal.

Learning problems

• Speech delay (60%)
• Receptive language delay (33%)
• Verbal apraxia (a motor speech disorder) (19%)
• Short-term memory problems (17%)
• Visual processing deficits (12%)
• Dysphasia/aphasia (10%)
• Auditory processing disorder (7%)

Neuropsychiatric disorders (see Note)

• Autism spectrum disorder (26%)
• Anxiety disorder (19%)
• Panic attacks (10%)
• Schizophrenia (5%-40%)
• Depression (at least 5%)
• Bipolar disorder (5%)

Individuals with the 3q29 deletion may exhibit more than one neuropsychiatric disorder. For example, roughly 50% of individuals with 3q29 deletion and ASD also report an anxiety disorder.

At least two case reports suggest that the age at onset for psychosis can be younger than the typical age at onset in the general population; Sagar et al reported psychosis in a boy age five years with 3q29 deletion [Sagar et al 2013] and Quintero-Rivera reported psychosis in a girl age ten years with 3q29 deletion [Quintero-Rivera et al 2010]. The average age of onset for schizophrenia and psychosis in the general population is 20-25 years.

Note: Data from neuropsychiatric phenotypes were obtained from 44 children, many of whom had not yet reached the age of risk for psychiatric phenotypes. Research in adults has established that the risk for schizophrenia is 40-fold increased [Mulle 2015, Mulle et al 2010]; the risk for bipolar disorder is also increased [Clayton-Smith et al 2010].

Recurrent ear infections (32%)

Gastrointestinal

• Feeding problems in childhood (42%) sometimes necessitating feeding by gastrostomy tube
• Gastroesophageal reflux disease (39%)
• Chronic constipation (22%)
• Dysphagia (12%)
• Hiatal hernia (5%)
• Chronic diarrhea (5%)

Dental

• Dental caries (24%), weak or soft tooth enamel (19%), enamel hypoplasia (10%)
• Abnormal dental spacing: crowded teeth (24%); widely spaced teeth (17%), large gap between central incisors (12%)
• Abnormal tooth size: large (10%), small (7%)
• Missing teeth (5%)

Genotype-Phenotype Correlations

No genotype-phenotype correlations for the 3q29 recurrent deletion are known.

Penetrance

Penetrance for the 3q29 recurrent deletion is not known. Reports of the deletion having been inherited from an unaffected parent suggest that while penetrance is high, it is likely not 100%.

It is unknown if penetrance differs in males and females.

Nomenclature

The 3q29 recurrent deletion may also be referred to as the “3q29 microdeletion syndrome” or the “3q29 deletion syndrome.”

Prevalence

The approximate prevalence is 1:30,000-1:40,000, based on a large population-based study in Iceland in which three of 101,655 individuals tested had the 3q29 recurrent deletion [Stefansson et al 2014]. Prevalence in other populations is not known.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with the 3q29 recurrent deletion, the following evaluations should be considered:

• Comprehensive developmental assessment including evaluation of cognitive, speech and language, motor, and social skills
• Psychiatric evaluation in individuals with evidence of neuropsychiatric manifestations including autism spectrum disorder (ASD)
• Assessment for feeding problems and nutrition; consultation with pediatric feeding specialists as needed
• Early consultation with a pediatric dentist
• Evaluation in infancy for evidence of congenital heart disease
• Consultation with a pediatric otolaryngologist as needed for recurrent otitis media
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

The following measures are appropriate:

• Early speech and language therapy to address speech delays
• Physical therapy as necessary to address fine and gross motor delays
• Individualized education program (IEP) for school-age children
• Care by a child psychiatrist for anxiety disorder and/or other neuropsychiatric manifestations
• Applied behavioral analysis or other treatment for manifestations of ASD
• Feeding therapy (including nutrition assessment) with a pediatric feeding specialist or behavioral pediatric psychologist; consideration of gastronomy tube for severe feeding problems and continued failure to thrive
• Routine management of dental caries, congenital heart defects, and recurrent ear infections

Surveillance

Continued assessment of:

• Feeding and nutrition
• Developmental milestones
• Cognitive development
• Possible psychiatric manifestations

Evaluation of Relatives at Risk

Parents and older and younger at-risk sibs of a proband should be tested for the 3q29 recurrent deletion. Parents or sibs may have the deletion, but with only mild or nonexistent developmental delay or intellectual disability. The average age at onset for schizophrenia is 20-25 years; thus, mildly affected individuals remain at risk for neuropsychiatric manifestations and would benefit from monitoring and clinical evaluation.

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. Note: There may not be clinical trials for this disorder.