Clinical Diagnosis

Because of the variability of the phenotypic features, the diagnosis of the 1q21.1 microdeletion is often made during chromosomal microarray analysis (CMA). Features that should prompt consideration of this diagnosis include:

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

Testing

Cytogenetic testing. The 1q21.1 microdeletion cannot be identified by routine analysis of G-banded chromosomes or other conventional cytogenetic banding techniques.

Molecular Genetic Testing

Critical region. The diagnosis of the 1q21.1 microdeletion is confirmed by the finding of a heterozygous 1.35-Mb microdeletion at chromosome 1q21.1 from position 145-146.35 Mb (NCBI Build 36).

There are three possible deletions involving this region (see Molecular Genetics). For this GeneReview the 1q21.1 microdeletion refers to the recurrent distal 1.35-Mb deletion in the 1q21.1 region. Thirty-nine of the 46 individuals presented in the literature with the recurrent 1.35-Mb deletion have clinical information regarding developmental delays, intellectual disability, and congenital anomalies [Brunetti-Pierri et al 2008, Mefford et al 2008].

Genes. At least eight genes listed in OMIM are included in the recurrent distal 1.35-Mb deletion in the 1q21.1 region: PRKAB2, FMO5, CHD1L, BCL9, ACP6, GJA5, GJA8, and GPR89B. No single gene mutations are known to cause the 1q21.1 microdeletion phenotype.

Clinical testing

Deletion/duplication analysis. The recurrent distal 1.35-Mb 1q21.1 microdeletion can be detected by any number of molecular methods that determine the copy number of sequences within the deleted region. Both whole-genome and targeted approaches can be applied:

• Deletion/duplication analysis. Most deletions are detected by chromosomal microarray analysis (CMA) performed as part of the evaluation of an individual with developmental delay, intellectual disability, dysmorphic features, or congenital anomalies. CMA using BAC clones or oligonucleotides or array-based heterozygosity testing with polymorphic DNA markers (i.e., SNPs) can detect the recurrent 1.35-Mb 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.
• Targeted deletion analysis. Targeting methods such as fluorescence in situ hybridization (FISH), quantitative polymerase chain reaction (qPCR), or multiplex ligation-dependent probe amplification (MLPA) can be used to interrogate the 1q21.1 region for the microdeletion if the deletion is suspected clinically, or to confirm the microdeletion after genomic microarray analysis. Targeted approaches can also be used to detect the deletion in relatives of the proband.
  
  The feasibility of sizing the microdeletion depends on the number and distribution of probes in the 1q21.1 region for any method used (CMA, quantitative PCR, MLPA). Sizing the microdeletion is important to confirm that it is the 1.35-Mb deletion and not another of the microdeletions known to occur in chromosome band 1q21.1 (see Molecular Genetics). It is not possible to size the microdeletion routinely using FISH.

Table 1. Summary of Molecular Genetic Testing Used to Detect the Recurrent 1q21.1 Deletion

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Chromosomal Region	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
1q21.1	Deletion/duplication analysis 2	Recurrent 1.35-Mb deletion	100%	Clinical

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a deletion or duplication that is present in the indicated chromosomal region

2. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, heterozygosity testing, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A genomic chromosomal microarray (CMA or array GH) analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

Interpretation of test results

Deletion analysis. Depending on the initial test used for detection, validation of the 1.35-Mb deletion by an independent method may be warranted. If high-density genomic microarray platforms have been used for the identification of the microdeletion, validation of the microdeletion may not be necessary, as it is unlikely that more than 50-100 adjacent targets show an abnormal copy number by chance. Such high-density platforms are also likely to confirm the microdeletion length as 1.35 Mb.

Testing Strategy

To establish the diagnosis in a proband requires detection of the 1.35-Mb deletion at chromosome 1q21.1. Most microdeletions are detected by CMA performed as part of the evaluation of developmental delay, intellectual disability, dysmorphic features, or congenital anomalies.

Note: The deletion cannot be identified by routine chromosome analysis.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the deletion in the proband and/or parent.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

Duplication of distal 1q21.1. Twenty-eight individuals with reciprocal duplications of the 1.35-Mb distal 1q21.1 deletion (defined by breakpoints at BP3-BP4; see Molecular Genetics) have been reported [Brunetti-Pierri et al 2008, Mefford et al 2008]; their occurrence is less frequent than the 1.35-Mb deletion based on these reports (aggregate total frequency of duplication vs. deletion of cohorts studied by CMA for developmental delay, intellectual disability, or congenital anomalies: 0.12% vs. 0.2%)

Features seen in individuals with this duplication may include macrocephaly or relative macrocephaly, frontal bossing, hypertelorism, learning or developmental delay, intellectual disability, and autistic features or autism spectrum disorder. In the study of Shaffer et al [2006] of two persons with inherited 1q21.1 duplications, one had dysmorphic features and the other had failure to thrive.

Greenway et al [2009] found three gains of distal 1q21.1 in 512 persons with tetralogy of Fallot, but none of these individuals had any extracardiac features or developmental delays.

The duplications can be inherited from a parent or occur de novo.

• In the study of Mefford et al [2008] of eight individuals, two (25%) were inherited from a normal parent, two (25%) were de novo, and four (50%) were of unknown status.
• In the study of Brunetti-Pierri et al [2008] of 14 individuals, eight (57%) were inherited (all parents were normal except one who had a learning disability, cataracts, glaucoma, depression, and anxiety); one (7%) was de novo; and five (36%) were of unknown status

Larger, overlapping 1q21.2 contiguous gene microdeletions. These microdeletions, sometimes termed Class Il deletions, are approximately 2-Mb microdeletions that involve both of the contiguous microdeleted regions associated with thrombocytopenia absent radius (TAR) syndrome and the 1.35-Mb distal deletion region.

• Eight probands and their affected parents and siblings have been described [Brunetti-Pierri et al 2008, Velinov & Dolzhanskaya 2010]. Features are variable, yet similar, to those of the distal 1.35-Mb 1q21.1 deletion, including dysmorphic features, developmental delays, and cardiac and genitourinary abnormalities.
• Clavicular pseudoarthrosis and an extra transverse crease of the fifth digit can also be seen [Velinov & Dolzhanskaya 2010]. Two of eight (25%) probands had de novo deletions.

Other larger deletions involving the distal 1q21.1 region have been reported. Greenway et al [2009] found one 3.9-Mb loss involving 1q21.1 in 512 persons with tetralogy of Fallot but no other extracardiac features.

Phenotypes associated with mutations in specific genes located within the recurrent distal 1.35-Mb deletion. Heterozygous GJA5 mutations or deletions have been identified in persons with:

• Atrial fibrillation [Gollob et al 2006]
• Structural cardiac defects [Christiansen et al 2004]

Heterozygous GJA8 mutations have been identified in persons with:

• Zonular pulverulent cataracts [Shiels et al 1998]
• Congenital nuclear progressive cataracts [Willoughby et al 2003]
• Nuclear pulverulent cataracts [Arora et al 2008]
• Cataract-microcornea syndrome [Devi & Vijayalakshmi 2006]

Natural History

Individuals with the 1q21.1 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.

The majority of persons with a 1q21.1 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. Intellectual disability, usually mild, is 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 approximately 50% of individuals with a 1q21.1 microdeletion.

Eye abnormalities are seen in 26% of individuals and may include strabismus, chorioretinal and iris colobomas, microphthalmia, hypermetropia, Duane anomaly, and various types of cataracts (e.g., congenital, nuclear pulverulent).

1q21.1 microdeletions involving GJA5 have previously been associated with cardiac defects, but the sizes of the deletions were not fully elucidated and may have involved additional genes [Christiansen et al 2004]. Three of 505 (0.6%) individuals with congenital heart disease were found to have a deletion involving GJA5; their cardiac defects included aortic coarctation, interrupted aortic arch-type A, and interrupted aortic arch-type B. Mefford et al [2008] reported individuals with patent ductus arteriosus, truncus arteriosus, ventricular and atrial septal defects, bicuspid aortic valve, dilation of ascending aorta, aortic insufficiency, coarctation of the aorta, and transposition of the great vessels in individuals with 1q21.1 deletions.

Genitourinary anomalies include vesicoureteral reflux, hydronephrosis, inguinal hernia, and cryptorchidism.

Skeletal malformations are variable and include joint laxity, brachydactyly with or without short distal phalanges, broad thumbs, clinodactyly of the fifth finger, club foot, 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 may be present. Seizures (e.g., tonic-clonic, absence) are seen in approximately 15% and often begin during the first year of life. One individual did not have seizures but had an EEG abnormality with slow waves over the anterior and central areas of both hemispheres [Mefford et al 2008].

Brain malformations are also described, including hydrocephalus and agenesis of the corpus callosum.

Sensorineural hearing loss has been reported in two individuals.

Psychiatric and behavioral abnormalities may also be present and include autism spectrum disorders, attention deficit hyperactivity disorder (10%), autistic features (8%), 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].

Genotype-Phenotype Correlations

No genotype-phenotype correlations are observed in those with the recurrent distal 1.35-Mb deletion in the 1q21.1 region.

Penetrance

Little information is available regarding penetrance of the 1.35-Mb deletion. Similar to several of the newly described microdeletions (e.g., 16p11.2, 15q13.3), the 1q21.1 microdeletion can be inherited from a parent with minimally abnormal or completely normal clinical findings. In addition, several relatives of probands with the same 1q21.1 microdeletion (e.g., siblings, cousins) 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; Author, personal observation]. This suggests that the 1q21.1 microdeletion has reduced penetrance and variable expressivity.

Prevalence

The frequency of the recurrent distal 1.35-Mb 1q21.1 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 recurrent distal 1.35-Mb deletion in the 1q21.1 region, the following evaluations should be considered:

• Ophthalmologic examination
• Cardiac evaluation
• Brain imaging in individuals with microcephaly, macrocephaly, and/or neurologic findings
• Renal ultrasound examination
• Comprehensive developmental assessment
• Psychiatric evaluation in individuals with evidence of mental illness
• Discussion of results with a medical geneticist or genetic counselor

Treatment of Manifestations

The following are indicated:

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

No specific antiepileptic or antipsychotic medications are indicated

Surveillance

Appropriate surveillance includes:

• Routine pediatric care
• Routine developmental assessments
• Monitoring of specific identified medical issues

Testing of Relatives at Risk

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

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

The recurrent distal 1.35-Mb 1q21.1 deletion is inherited in an autosomal dominant manner, with 18%-50% of deletions occurring de novo.

Risk to Family Members

Parents of a proband

• Mefford et al [2008] found that in 50% (7/14) of the probands for whom parental testing was possible, a parent also had the microdeletion. Therefore, the other 50% (7/14) of the probands had a de novo microdeletion. 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 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 a 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 microdeletion is inherited, the parent has a normal phenotype.
• 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 parents may have (a) germline mosaicism OR (b) low-level somatic mosaicism that also includes the germline.

Sibs of a proband. Because parents who have the microdeletion can be clinically unaffected, the risk to the sibs of a proband depends on the deletion status of the parents:

• If a parent has the microdeletion, each sib is at a 50% risk of inheriting the microdeletion. An affected sib may show findings similar to those of the proband but could also have a milder or more severe phenotype.
• In the unlikely event that a parent has germline mosaicism for the 1.35-Mb deletion or a balanced structural chromosome rearrangement involving the 1q21.1 region, the risk to sibs is increased and depends on the specific chromosome rearrangement.

Offspring of a proband. Individuals who have the 1.35-Mb deletion are expected to have a 50% chance of transmitting the deletion to each child.

Other family members. The risk to other family members depends on their deletion status.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal 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 1.35-Mb 1q21.1 microdeletion.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal testing may be offered to unaffected parents who have had a child with a 1.35-Mb 1q21.1 microdeletion because of the recurrence risk (probably <1%) associated with the possibility of germline mosaicism.

Prenatal testing is technically feasible. Preparations from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks' gestation or CVS at approximately ten to 12 weeks' gestation can be analyzed using CMA or FISH in the same manner described in Molecular Genetic Testing.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

Similar to other genomic disorders (e.g., deletions and reciprocal duplications of 22q11.2, 7q11.2, 15q11q13, 15q13.3, 16p11.2, 17q21.31, etc), the breakpoints of the 1q21.1 microdeletion commonly occur within flanking segmental duplications. In all these cases, the flanking segmental duplications in direct orientation share a high degree of sequence identity, which predisposes to rearrangements by non-allelic homologous recombination (NAHR). NAHR occurs from misalignment of and subsequent recombination between the flanking segmental duplications. The result is a deletion and a duplication of the sequences between the flanking segments, which is 1.35 Mb in the case of 1q21.1 microdeletion [Emanuel & Shaikh 2001, Lupski & Stankiewicz 2005].

In the 1q21.1 region, there are four copies of segmental duplications in direct orientation, each with high sequence identify. These noncontiguous segmental duplication elements are termed BP1, BP2, BP3, and BP4, so named because they are recombination breakpoint hotspots for deletion and duplication of sequences between the BP elements [Mefford et al 2008].

• The breakpoints of the distal 1.35-Mb microdeletion described in this GeneReview are between BP3 and BP4 [Mefford et al 2008]; these are sometimes referred to as Class I deletions.
• A smaller, more proximal deletion has been associated with thrombocytopenia absent radius (TAR) syndrome, which occurs between BP2 and BP3.
• A third type of deletion, sometimes called Class II deletions, occurs between BP2 and BP4. These approximately 2-Mb deletions involve both the TAR-associated and the 1.35 Mb distal 1q21.1 chromosomal regions [Velinov & Dolzhanskaya 2010]. (See Genetically Related Disorders.)

At least eight genes listed in OMIM are included in distal 1q21.1 deletions: PRKAB2, FMO5, CHD1L, BCL9, ACP6, GJA5, GJA8, and GPR89B. Mutations in no single gene are associated with 1q21.1 microdeletion syndrome, but haploinsufficiency of one or more of the deleted genes likely contributes to the phenotype.

• Heterozygous GJA5 mutations have been identified in some persons with atrial fibrillation [Gollob et al 2006].
• Heterozygous GJA8 mutations are found in persons with zonular pulverulent cataracts [Shiels et al 1998], congenital nuclear progressive cataracts [Willoughby et al 2003], nuclear pulverulent cataracts [Arora et al 2008], and cataract-microcornea syndrome [Devi & Vijayalakshmi 2006].

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Suggested Reading

1. Kirov G. The role of copy number variation in schizophrenia. Expert Rev Neurother. 2010;10:25–32. [PubMed: 20021318]
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Revision History

• 24 February 2011 (me) Review posted live
• 30 November 2010 (che) Original submission