Clinical characteristics.

3q29 recurrent deletion is characterized by neurodevelopmental and/or psychiatric manifestations including mild-to-moderate intellectual disability (ID), autism spectrum disorder (ASD), anxiety disorders, attention-deficit/hyperactivity disorder (ADHD), executive function deficits, graphomotor weakness, and psychosis/schizophrenia. Age at onset for psychosis or prodrome can be younger than the typical age at onset in the general population. Neurodevelopmental and psychiatric conditions are responsible for the majority of the disability associated with the 3q29 deletion. Other common findings are failure to thrive and feeding problems in infancy that persist into childhood, gastrointestinal disorders (including constipation and gastroesophageal reflux disease [GERD]), ocular issues, dental anomalies, and congenital heart defects (especially patent ductus arteriosus). Structural anomalies of the posterior fossa may be seen on neuroimaging. To date more than 200 affected individuals have been identified.

Diagnosis/testing.

The diagnosis of the 3q29 recurrent deletion is established by identification of a heterozygous 1.6-Mb deletion 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/occupational therapy as needed to address motor issues; individualized education program for school-age children; care by a child psychiatrist/psychologist as needed for neuropsychiatric disorders with transfer of care to an adult psychiatrist when appropriate; cognitive behavioral therapy to address social disability and/or anxiety; adaptive behavior as needed; applied behavioral analysis for ASD; medication as needed for anxiety, ADHD, or psychosis; standard treatment of seizures; feeding therapy and consideration of gastrostomy tube as needed; routine management of musculoskeletal issues, GERD, strabismus, dental issues, congenital heart defects, recurrent ear infections, and epistaxis; consider behavioral treatment for enuresis; implement healthy sleep hygiene; family support.

Surveillance: At each visit: monitor developmental progress, educational needs, growth, nutrition, and feeding; assess for seizures, gastrointestinal issues, otitis, enuresis, and/or sleep issues. Annual assessment for neuropsychiatric manifestations and scoliosis; annual ophthalmology examination; dental examination every six months.

Evaluation of relatives at risk: If one of the proband's parents has the 3q29 recurrent deletion, it is appropriate to test at-risk sibs of the proband in order to identify those who would benefit from close assessment/monitoring of developmental milestones (in children) and monitoring for neuropsychiatric manifestations (in children and adults).

Genetic counseling.

3q29 recurrent deletion is an autosomal dominant disorder typically caused by a de novo deletion. If the proband represents a simplex case (i.e., a single affected family member) and neither parent has the 3q29 recurrent deletion or a balanced chromosome rearrangement, the recurrence risk to sibs is low (presumed to be <1%) but greater than that of the general population because of the possibility of parental mosaicism for the deletion. Each child of an individual with the 3q29 recurrent deletion has a 50% chance of inheriting the deletion. Once the 3q29 recurrent deletion has been identified in an affected family member, prenatal testing for a pregnancy at increased risk for the 3q29 recurrent deletion and preimplantation genetic testing are possible.

Suggestive Findings

The 3q29 recurrent deletion should be considered in individuals with the following clinical findings [Sanchez Russo et al 2021]:

• Developmental delay typically including speech and motor delays
• Intellectual disability; mild to moderate (34%), severe (<5%)
• Neuropsychiatric disorders including attention-deficit/hyperactivity disorder, anxiety disorders, and/or autism spectrum disorder (ASD)
• Failure to thrive and/or feeding problems in infancy that persist into childhood
• Gastrointestinal disorders including gastroesophageal reflux disease
• Ocular issues
• Dental anomalies
• Congenital heart defects, especially patent ductus arteriosus
• Subtle facial dysmorphology including a prominent forehead, prominent nasal tip, and thin vermilion of the upper lip [Mak et al 2021]

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

Establishing the Diagnosis

The diagnosis of the 3q29 recurrent deletion is established by identification of a heterozygous 1.6-Mb deletion at chromosome 3q29, typically by 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).

Note: (1) Since these deletions are recurrent and mediated by segmental duplications, the unique genetic sequence that is deleted is the same in all individuals with the deletion; however, the reported size of the deletion: (a) may be larger if adjacent segmental duplications are included in the size; and (b) may vary based on the design of the microarray used to detect it (see Molecular Pathogenesis). (2) The phenotype of significantly larger or smaller deletions within this region may be clinically distinct from the 3q29 recurrent deletion. (3) Although pathogenic variants in a single gene in the 3q29 region are not causative of the 3q29 recurrent deletion, several genes of interest have been identified (see Molecular Genetics).

Genomic testing methods that determine the copy number of sequences can include 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.

• CMA using oligonucleotide 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 3q29 region.
  Note: (1) Most individuals with a 3q29 recurrent deletion are identified by CMA performed in the context of evaluation for DD, ID, or ASD. (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, multiplex ligation-dependent probe amplification, 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 this region. (2) It is not possible to size the deletion routinely by use of targeted methods.

Clinical Description

3q29 recurrent deletion is characterized by neurodevelopmental and/or psychiatric manifestations. Other common findings are failure to thrive, feeding problems, gastrointestinal disorders, ocular issues, dental anomalies, and congenital heart defects. To date more than 200 affected individuals have been identified. The summary below is based on the comprehensive review of all reported individuals in Cox & Butler [2015], the self-reported findings in 44 individuals from the 3q29 Deletion Registry [Glassford et al 2016], and deep phenotyping of 32 individuals [Sanchez Russo et al 2021].

Developmental delay. Developmental milestones are delayed between six to twelve months.

Speech delay is reported in 60% of individuals. Speaking single words occurs at an average age of 23 months. Receptive language delay is reported in 33% and verbal apraxia (a motor speech disorder) is reported in 19%. Dysphasia/aphasia is reported in 10%. Only one of 44 individuals reported to have the 3q29 deletion is completely nonverbal [Glassford et al 2016].

Motor delay. Hypotonia is reported in 34% during the first year of life. Independent walking is usually achieved at age 20 months. Despite cerebellar anomalies observed on MRI, no pronounced ataxia or gait abnormalities are observed [Sanchez Russo et al 2021].

Cognitive issues. Children with the 3q29 deletion show a range of intellectual ability, with approximately 34% having mild-to-moderate intellectual disability (ID). Fewer than 5% have severe ID. IQ measures reveal a wide differential between subtest scores, with on average a 14-point absolute difference between verbal and nonverbal IQ subtest scores. Although speech delay is common in individuals with the 3q29 recurrent deletion, among individuals age six years and older, 61% have a verbal subtest score that is higher than their nonverbal subtest score (see medRxiv). Sixty-six percent of children with the 3q29 recurrent deletion have IQ scores within the normal range; however, these individuals may have substantial neurodevelopmental and psychiatric disability that is not captured by IQ measures.

Neuropsychiatric disorders

• ASD (38%). Individuals with the 3q29 recurrent deletion without a diagnosis of autism may exhibit social disability [Pollak et al 2019].
• Anxiety disorder (40%)
• Schizophrenia (at least 20%) [Mulle et al 2010, Mulle 2015, Sanchez Russo et al 2021]
• ADHD (63%)
• Bipolar disorder (5%)

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

The age at onset for psychosis or prodrome can be younger than the typical age at onset in the general population. Early-onset psychosis was reported in one boy age five years [Sagar et al 2013] and one girl age ten years with the 3q29 deletion [Quintero-Rivera et al 2010]. Murphy et al [2020] reported attenuated psychosis syndrome in a boy age eight years. The average age of onset for schizophrenia and psychosis in the general population is 20-25 years.

Executive function deficits. Executive function, or the higher-order cognitive processes that regulate planning, decision making, and goal-oriented behavior, are substantially impaired in nearly half of individuals with the 3q29 recurrent deletion.

Graphomotor weakness. Graphomotor skills, or the skills required for writing and other fine-motor tasks, are substantially impaired in most individuals with the 3q29 recurrent deletion and can lead to difficulties in language learning and literacy. If not recognized, graphomotor weakness will present challenges in educational settings.

Seizures occur in 13% of reported individuals and are generally mild and respond to standard anti-seizure treatment. Seizures may be atonic (3%), febrile (6%), nocturnal (3%), or unspecified (3%).

Musculoskeletal anomalies include chest deformities such as pectus excavatum (25%) and pectus carinatum (9%). There is elevated prevalence of scoliosis (6%). Lower-extremity anomalies are reported in 72%, including abnormal toes (28%), medial rotation of the medial malleolus (31%), and pes planus (31%). Upper-extremity anomalies are reported in 47%, such as long, thin fingers (25%) and abnormal palmar creases (9%).

Gastrointestinal issues. Pediatric feeding problems are present in 60% and failure to thrive in 44%, sometimes necessitating feeding by gastrostomy tube (see medRxiv). Additional gastrointestinal issues include gastroesophageal reflux disease (50%), chronic constipation (41%), dysphagia (12%), hiatal hernia (5%), and chronic diarrhea (5%).

Ocular anomalies include astigmatism, hypermetropia, myopia, and strabismus. Strabismus is present in 28% of individuals with the 3q29 deletion; of these, approximately 30% require surgical correction.

Dental anomalies include dental caries (24%), weak tooth enamel (19%), enamel hypoplasia (10%), and missing teeth (5%). Abnormal dental spacing is also reported with crowded teeth (24%), widely spaced teeth (17%), and diastema between the central incisors (12%). Abnormally large teeth in reported in 10%, and abnormally small teeth in 7%.

Allergies include seasonal allergies (16%) and food allergies (13%). Rarely, individuals report drug allergies (3%). Immunoglobulin (Ig) deficiencies including IgA deficiency (3%) and IgG deficiency (3%) have been reported.

Congenital heart defects include patent ductus arteriosus (12%), ventricular septal defect (5%), and pulmonary valvar stenosis (5%).

Craniofacial features. Systematic characterization of craniofacial features on a cohort of 31 individuals with the 3q29 recurrent deletion showed a subtle but seemingly non-random pattern of craniofacial findings [Mak et al 2021]. Dysmorphic features were seen in the vast majority of individuals. The most common findings included prominent forehead and wide nose in almost half of individuals, prominent nasal tip in approximately 35%, and thin vermilion of the upper lip in approximately 25% of individuals. Other common findings include low-hanging columella (23%), prominent nasal bridge (23%), and incisor macrodontia (23%). Phenotyping technology (Face2gene), successfully differentiated between an individual with the 3q29 deletion and a control individual 87.3% of the time (p-value of 0.006).

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%. However, in reports of inherited 3q29 deletion, transmitting parents are rarely assessed for neurodevelopmental and psychiatric phenotypes. One transmitting parent who was assessed with a comprehensive phenotyping protocol was found to have schizoaffective disorder, ADHD, panic disorder, social anxiety disorder, clinically significant deficits in executive function, and significant delays in adaptive behavior – all previously undiagnosed. This individual had an average IQ score of 94 [Murphy et al 2020].

Prevalence

The approximate prevalence is 1:30,000-1:40,000, based on (1) a large population-based study in Iceland in which three of 101,655 individuals tested had the 3q29 recurrent deletion [Stefansson et al 2014] and (2) prevalence in the UK Biobank, in which five individuals with the 3q29 recurrent deletion were identified in a population-based cohort of 152,728 individuals [Kendall et al 2017]. Prevalence in other populations is not known.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with the 3q29 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

Surveillance

Evaluation of Relatives at Risk

If genomic testing detects the 3q29 recurrent deletion in one of the proband's parents, it is appropriate to clarify the genetic status of older and younger sibs of the proband in order to identify those who would benefit from close assessment/monitoring of developmental milestones (in children) and monitoring for neuropsychiatric manifestations (in children and adults).

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.

Mode of Inheritance

The 3q29 recurrent deletion is an autosomal dominant disorder typically caused by a de novo deletion.

Risk to Family Members

Parents of a proband

• Although most deletions are de novo, inherited deletions have been reported [Cox & Butler 2015]. Of the 28 families with the 3q29 recurrent deletion in which parents have undergone genomic testing, the deletion was confirmed to be inherited in two families (7%).
• Evaluation of the parents by genomic testing that will detect the 3q29 recurrent deletion present in the proband is recommended to confirm their genetic status and to allow reliable recurrence risk counseling. (Note: A parent who has a 3q29 recurrent deletion may have only mild manifestations of the disorder or have phenotypes that go undetected because appropriate evaluations have not been conducted.) Testing for a balanced chromosome rearrangement in the parents is also recommended.
• If neither parent has the 3q29 recurrent deletion identified in the proband or a balanced chromosome rearrangement, the following possibilities should be considered:
  • The proband has a de novo deletion.
  • The proband inherited the deletion from a parent with germline (or somatic and germline) mosaicism. Somatic/germline mosaicism was reported in one father of a proband with the 3q29 recurrent deletion [Petrin et al 2011].
    Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a deletion that is present in the germ cells only.

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

• If the proband represents a simplex case (i.e., a single affected family member) and neither parent has the 3q29 recurrent deletion or a balanced chromosome rearrangement, the recurrence risk to sibs is low (presumed to be <1%) but greater than that of the general population because of the possibility of parental germline mosaicism for the deletion.
• If one of the parents has the 3q29 recurrent deletion, the risk to each sib of inheriting the deletion is 50%. However, it is not possible to reliably predict the phenotype in a sib who inherits the deletion, as the phenotypic spectrum associated with the 3q29 recurrent deletion can vary widely among family members [Digilio et al 2009, Li et al 2009, Murphy et al 2020].
• If one of the parents has a balanced chromosome rearrangement, the risk to sibs of having the 3q29 recurrent deletion is increased and depends on the specific chromosome rearrangement and the possibility of other variables.

Offspring of a proband. Each child of an individual with the 3q29 recurrent deletion has a 50% chance of inheriting 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 3q29 recurrent deletion or a balanced chromosome rearrangement, the parent's family members may also have the deletion or the chromosome rearrangement.

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 3q29 recurrent deletion. Note: If a parent is known to have a balanced chromosome rearrangement, genetic counseling should also address reproductive risks associated with balanced chromosome rearrangements.

Prenatal Testing and Preimplantation Genetic Testing

Pregnancies known to be at increased risk for the 3q29 recurrent deletion. Once the 3q29 recurrent deletion has been identified in an affected family member, prenatal testing for a pregnancy at increased risk for the 3q29 recurrent deletion and preimplantation genetic testing are possible.

Prenatal testing or preimplantation genetic testing using genomic testing that will detect the 3q29 recurrent deletion found in the proband may be offered when:

• A parent has the 3q29 recurrent deletion;
• The parents do not have the recurrent deletion but have had a child with the 3q29 recurrent deletion. In this instance, the recurrence risk associated with the possibility of parental germline mosaicism or other predisposing genetic mechanisms is probably slightly greater than that of the general population (though still presumed to be <1%).

Pregnancies not known to be at increased risk for 3q29 recurrent deletion. CMA performed in a pregnancy not known to be at increased risk may detect the 3q29 recurrent deletion.

Note: Regardless of whether a pregnancy is known or not known to be at increased risk for the 3q29 recurrent deletion, prenatal test results cannot reliably predict the phenotype.

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

Deletion mechanism. Deletion breakpoints are usually found in low-copy repeats (LCRs) that flank the 3q29 recurrent deletion region. Nonallelic homologous recombination (NAHR) occurs when LCRs flanking the region misalign during meiosis followed by unequal crossing over between the LCRs. This process can produce gametes with the recurrent deletion or the reciprocal recurrent duplication. Breakpoints of the 3q29 recurrent deletion lie within the flanking LCRs, suggesting that the deletion arises through NAHR.

Genes of interest in this region. It is not currently known which of the genes in the region is responsible for the phenotype. However, there are several genes of interest: DLG1 and PAK2 are of interest for the neurodevelopmental and psychiatric phenotypes. It is hypothesized that 3q29 deletion phenotypes result from the loss of multiple genes (i.e., loss of both DLG1 and PAK2). A mouse model of the 3q29 deletion has deficits in learning, memory, and social behaviors [Rutkowski et al 2021]. Mouse models with loss of DLG1 alone [Rutkowski et al 2021] or PAK2 alone [Wang et al 2018] do not fully recapitulate the 3q29 deletion phenotype.

• DLG1 plays a role in trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors to the neuronal membrane.
• PAK2 is involved in mediating molecular processes such as neuron migration, outgrowth, and spine morphogenesis, and also controls neuronal differentiation.

Author Notes

The 3q29 Project (sites.rutgers.edu/mulle), a large interdisciplinary collaboration led by PI Jennifer Mulle, is devoted to understanding the phenotypic spectrum, natural history, and molecular mechanism of 3q29 deletion syndrome. For information about ongoing research studies, contact Dr Mulle at ude.sregtur@ellum.refinnej.

Acknowledgments

Research into 3q29 deletion syndrome has been generously supported by the NIH (NIMH: R01 MH110701, R01 MH118534-01; NIGMS: R01 GM097331) and PCORI (EAIN-00097). We also wish to acknowledge the probands affected by the 3q29 deletion and their families; their participation and engagement in research has been critical for advancing our understanding of the syndrome.

Author History

T Lindsey Burrell, PhD (2021-present)
Edwin H Cook, MD; University of Illinois at Chicago (2016-2021)
Joseph F Cubells, MD, PhD (2021-present)
Michael J Gambello, MD, PhD (2016-present)
Megan Glassford, MMSc; Emory University School of Medicine (2016-2021)
Cheryl Klaiman, PhD (2021-present)
Longchuan Li, PhD (2021-present)
Jennifer Gladys Mulle, MHS, PhD (2016-present)
Melissa M Murphy, PhD (2021-present)
Timothy P Rutkowski, PhD; Emory University School of Medicine (2016-2021)
Rossana Sanchez Russo, MD (2021-present)
Celine A Saulnier, PhD (2021-present)
Sarah Shultz, PhD (2021-present)
Elaine F Walker, PhD (2021-present)
Stormi White, PsyD (2021-present)

Revision History

• 1 July 2021 (sw) Comprehensive update posted live
• 22 September 2016 (bp) Review posted live
• 30 November 2015 (jgm) Original submission

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