Clinical characteristics.

The 1q21.1 recurrent microdeletion itself does not appear to lead to a clinically recognizable syndrome as some persons with the deletion have no obvious clinical findings and others have variable findings that most commonly include microcephaly (50%), mild intellectual disability (30%), mildly dysmorphic facial features, and eye abnormalities (26%). Other findings can include cardiac defects, genitourinary anomalies, skeletal malformations, and seizures (~15%). Psychiatric and behavioral abnormalities can include autism spectrum disorders, attention deficit hyperactivity disorder, autistic features, and sleep disturbances.

Diagnosis/testing.

The distal 1.35-Mb 1q21.1 recurrent microdeletion can be detected by any number of molecular methods that determine the copy number of sequences within the deleted region, including chromosomal microarray analysis (CMA) using oligonucleotides or polymorphic DNA markers (i.e., SNPs). Fluorescence in situ hybridization (FISH) analysis may be used to test relatives of a proband known to have this deletion.

Management.

Treatment of manifestations: Routine treatment of ophthalmologic, cardiac, and neurologic findings; speech, occupational, and physical therapies as appropriate; specialized learning programs to meet individual needs; anti-seizure or antipsychotic medication as needed.

Surveillance: Routine pediatric care; routine developmental assessments; monitoring of specific identified medical issues.

Genetic counseling.

The recurrent distal 1.35-Mb 1q21.1 microdeletion is inherited in an autosomal dominant manner. Between 18% and 50% of deletions occur de novo. The microdeletion can be inherited from either parent; a parent with the microdeletion may show a normal phenotype or an abnormal phenotype that is similar to but usually less severe than that of his/her child. Recurrence risk for future pregnancies for parents who do not have the microdeletion is low (probably <1%) but greater than that of the general population because of the possibility of germline mosaicism.

Suggestive Findings

1q21.1 recurrent microdeletion should be suspected in individuals with the following features:

• Developmental delays
• Mild-to-moderate intellectual disability
• Mild dysmorphic facial features (frontal bossing, deep-set eyes, bulbous nose)
• Microcephaly

Establishing the Diagnosis

The diagnosis of the 1q21.1 recurrent microdeletion is established by detection of the recurrent distal 1.35-Mb heterozygous microdeletion at the approximate position of 145-146.35 Mb in the reference genome (NCBI Build 36).

Note: The phenotype of significantly larger or smaller deletions within this region may be clinically distinct from the 1q21.1 recurrent microdeletion (see Genetically Related Disorders).

Although several genes of interest (PRKAB2, CHD1L, BCL9, GJA5, GJA8) are within the distal 1.35-Mb recurrent microdeletion, 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 by fluorescence in situ hybridization (FISH). Note: The 1q21.1 recurrent microdeletion 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 1q21.1 region.
  Note: (1) Most individuals with the 1q21.1 recurrent microdeletion are identified by CMA performed in the context of developmental delay, intellectual disability, or autism spectrum disorders. (2) Prior to 2008 many CMA platforms did not include coverage of the 1q21.1 region and thus may not have detected this deletion.
• 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 the1q21.1 recurrent microdeletion.
  Note: (1) Targeted deletion testing is not appropriate for an individual in whom the 1q21.1 recurrent microdeletion 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.

Evaluating at-risk relatives. FISH, qPCR, or other quantitative methods of targeted deletion analysis can be used to identify the 1q21.1 recurrent microdeletion in at-risk relatives of the proband. Testing parental samples is important in determining recurrence risk (see Genetic Counseling).

Clinical Description

Individuals with the 1q21.1 recurrent microdeletion may have a wide range of clinical manifestations. The most common findings include developmental delay and mildly dysmorphic facies. However, there is not a clinically recognizable syndrome, as a subset of persons with the deletion do not have obvious clinical findings.

Clinical information from three reports involving 55 probands with the 1q21.1 recurrent microdeletion is summarized in Table 2 [Brunetti-Pierri et al 2008, Mefford et al 2008, Bernier et al 2015].

The majority of persons with the 1q21.1 recurrent microdeletion have developmental delay. Most delays are mild and may involve global or specific areas, particularly gross motor development. Some may also have generalized learning disabilities throughout life. Mild intellectual and learning disabilities are seen in approximately 30% of affected individuals.

Dysmorphic craniofacial features are a common finding but are highly variable and therefore not easily recognizable. The facial features may include frontal bossing, deep-set eyes, epicanthal folds, prominent and/or large nasal bridge with bulbous tip, long philtrum, and highly arched palate. Microcephaly is described in 39% of individuals with the 1q21.1 recurrent microdeletion.

Eye abnormalities are seen in 33% of individuals and may include strabismus, chorioretinal and iris colobomas, microphthalmia, hypermetropia, Duane anomaly, and various types of cataracts (e.g., congenital, nuclear pulverulent).

Several reported individuals with the 1q21.1 recurrent microdeletion have cardiac defects, including patent ductus arteriosus, truncus arteriosus, ventricular and atrial septal defects, tetralogy of Fallot, bicuspid aortic valve, dilation of ascending aorta, aortic insufficiency, coarctation of the aorta, interrupted aortic arch, anomalous origin of the right coronary artery, pulmonary valve stenosis, and transposition of the great vessels in individuals with 1q21.1 deletions [Digilio et al 2013].

Genitourinary anomalies include vesicoureteral reflux, hydronephrosis, inguinal hernia, and cryptorchidism. Two individuals with the deletion had Mayer-Rokitansky-Kuster-Hauser syndrome [Chen et al 2015].

Skeletal malformations are variable and include craniosynostosis, scoliosis, joint laxity, brachydactyly with or without short distal phalanges, broad thumbs, clinodactyly of the fifth finger, clubfoot, small feet, pes planus, broad or duplicated/bifid great toes, overlapping or syndactyly of the toes, and polydactyly of the hands or feet.

Most affected individuals have a normal neurologic physical examination, but hypotonia and tremors are fairly common features. Seizures (e.g., tonic-clonic, absence) are seen in approximately 16% and often begin during the first year of life.

Brain malformations that have been described include hydrocephalus and agenesis of the corpus callosum.

Sensorineural hearing loss has been reported in five individuals.

Psychiatric and behavioral abnormalities that may be present include autism spectrum disorders, attention deficit hyperactivity disorder, anxiety and mood disorders, and sleep disturbances. In addition, distal 1q21.1 microdeletions have been identified in 0.2%-0.6% of persons with schizophrenia [International Schizophrenia Consortium 2008, Stefansson et al 2008, Walsh et al 2008, Rees et al 2014].

Genotype-Phenotype Correlations

No genotype-phenotype correlations are observed in those with the 1q21.1 recurrent microdeletion.

Penetrance

Little information is available regarding penetrance of the 1q21.1 recurrent microdeletion. Similar to several other recurrent microdeletions (e.g., 16p11.2, 15q13.3), the 1q21.1 recurrent microdeletion can be inherited from a parent with minimally abnormal or completely normal clinical findings. In addition, several relatives of probands (e.g., sibs, cousins) with the same 1q21.1 microdeletion have a normal phenotype or only mild manifestations [Christiansen et al 2004; Shaffer et al 2006; Brunetti-Pierri et al 2008; Mefford et al 2008; Bernier et al 2015; Authors, personal observation]. This suggests that the 1q21.1 recurrent microdeletion has reduced penetrance and variable expressivity.

Prevalence

The frequency of the 1q21.1 recurrent microdeletion is approximately 0.2% (46/22,563) of individuals with developmental delays, intellectual disabilities, and/or congenital anomalies evaluated by CMA [Brunetti-Pierri et al 2008, Mefford et al 2008].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with the 1q21.1 recurrent microdeletion, the following evaluations should be considered:

• Ophthalmologic examination if there are concerns about vision
• Cardiac evaluation if there are suggestive features clinically or on physical examination
• Brain imaging if microcephaly, macrocephaly, and/or neurologic findings are present
• Renal ultrasound examination
• Comprehensive developmental assessment for motor and language delays, which may include evaluations for autism spectrum disorders, intellectual disability, ADHD, and hearing loss
• Neurology consultation if significant hypotonia, seizures, tics, or tremors are present
• Psychiatric evaluation if evidence of mental illness is present
• Consultation with a medical geneticist and/or genetic counselor

Treatment of Manifestations

The following are indicated:

• Routine treatment of ophthalmologic, cardiac, and neurologic findings
• Speech, occupational, and physical therapies, as appropriate
• Specialized learning programs to meet individual needs

No specific anti-seizure or antipsychotic medications are indicated.

Surveillance

Appropriate surveillance includes the following:

• Routine pediatric care
• Routine developmental and learning assessments
• Monitoring of any specific medical issues that are identified

Evaluation of Relatives at Risk

Using genomic testing that will detect the 1q21.1 recurrent microdeletion found in the proband, it is appropriate to evaluate the 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. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

The 1q21.1 recurrent microdeletion is inherited in an autosomal dominant manner, with 18%-50% of deletions occurring de novo and 50%-82% inherited from a parent.

Risk to Family Members

Parents of a proband

• Evaluation of the parents by genomic testing that will detect the 1q21.1 recurrent microdeletion present in the proband is recommended.
• Mefford et al [2008] found that in 50% (7/14) of the probands for whom parental testing was possible, a parent also had the recurrent microdeletion. Therefore, in the other 50% (7/14) the microdeletion was de novo. In another study [Brunetti-Pierri et al 2008], 82% (9/11) of probands had inherited the microdeletion, and in 18% (2/11) it was de novo. Note: In 4/15 probands the parental status was unknown.
  The recurrent microdeletion can be inherited from either parent, and it does not appear that the phenotypic severity varies with the parent of origin. A parent with the recurrent microdeletion may show an abnormal phenotype similar to their child but in general is less severely affected. In approximately 25% of instances in which the recurrent microdeletion is inherited, the parent has a normal phenotype.
• A parent may have either (a) germline mosaicism or (b) low-level somatic mosaicism that also includes the germline.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the parents.
• If the 1q21.1 recurrent microdeletion 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 microdeletion.
• If one of the parents has the 1q21.1 recurrent microdeletion, the risk to each sib of inheriting the microdeletion is 50%. However, it is not possible to reliably predict the phenotype of the individual.

Offspring of a proband. Offspring of an individual with the 1q21.1 recurrent microdeletion have a 50% chance of inheriting the microdeletion.

Other family members

• The risk to other family members depends on the genetic status of the proband’s parents.
• If a parent has the 1q21.1 recurrent microdeletion, the parent's family members may also have the microdeletion.

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 have or are at risk of having a child with the 1q21.1 recurrent microdeletion.

Prenatal Testing and Preimplantation Genetic Testing

Pregnancies known to be at increased risk for the recurrent microdeletion. Prenatal testing using genomic testing that will detect the 1q21.1 recurrent microdeletion found in the proband may be offered when:

• A parent has the recurrent microdeletion;
• The parents do not have the recurrent microdeletion but have had an affected child with the recurrent microdeletion. In this instance, the recurrence risk associated with the possibility of parental germline mosaicism or other predisposing genetic mechanisms is probably <1%.

Pregnancies not known to be at increased risk for 1q21.1 recurrent microdeletion. CMA performed in a pregnancy not known to be at increased risk may detect the recurrent microdeletion.

Note: Prenatal test results cannot reliably predict the phenotype whether the pregnancy is known or not known to be at increased risk for 1q21.1 recurrent microdeletion.

Preimplantation genetic testing may be an option for some families in which the 1q21.1 recurrent microdeletion has been identified.

Molecular Pathogenesis

Revision History

• 12 November 2015 (bp) Comprehensive update posted live
• 24 February 2011 (bp) Review posted live
• 30 November 2010 (che) Original submission

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