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16p12.2 Microdeletion

Synonym: 16p12.1 Microdeletion

, MBBS, PhD, , MD, MS, and , MS.

Author Information

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Summary

Clinical characteristics.

16p12.2 microdeletion is characterized by variable clinical findings that do not constitute a recognizable syndrome. Of note, the significant bias in ascertainment of individuals undergoing clinical chromosomal microarray analysis (i.e., children with intellectual disability and developmental delay; individuals with schizophrenia) makes it difficult to accurately associate specific phenotypes to the 16p12.2 microdeletion. Findings commonly observed in children (probands) with this deletion include: developmental delay, cognitive impairment (ranges from mild to profound), growth impairment (including short stature), cardiac malformations, epilepsy, and psychiatric and/or behavioral problems. Other findings can include: hearing loss, dental abnormalities, renal and genital anomalies (the latter in males), and cleft palate ± cleft lip.

Diagnosis/testing.

The diagnosis of 16p12.2 microdeletion is established by demonstration of a 520 kb heterozygous deletion on chromosome 16p12.2 on CMA or other genomic analyses.

Management.

Treatment of manifestations: Treatment is directed to specific problems identified and may include developmental therapies; routine treatment of cardiac malformations, epilepsy, psychiatric and behavioral problems, hearing loss, and other malformations (e.g., oro-facial clefting; renal, genitourinary, and dental anomalies).

Surveillance: Periodic: developmental evaluations; monitoring of cardiac, renal, urologic, and/or dental abnormalities, as needed; reevaluation by a clinical geneticist

Genetic counseling.

The 16p12.2 microdeletion is inherited in an autosomal dominant manner. The majority (~95%) of individuals with this microdeletion have inherited the microdeletion from a parent (who may or may not have clinical features related to the microdeletion). If a parent is heterozygous for the 16p12.2 microdeletion, the risk that the sibs of a proband would inherit the microdeletion is 50%; however, the risk that sibs would be affected is less than 50% because of reduced penetrance for the microdeletion. If a 16p12.2 microdeletion has been identified in a family member, prenatal testing for pregnancies at increased risk is possible; however, it is not possible to reliably predict phenotype based on the laboratory finding of a 16p12.2 microdeletion.

Diagnosis

No formal diagnostic criteria have been established for 16p12.2 microdeletion.

Because of the variable clinical presentation of 16p12.2 microdeletion, the diagnosis is made by detection of 16p12.2 microdeletion on chromosomal microarray analysis (CMA) or other genomic analyses.

Suggestive Findings

Clinical features that suggest a possible 16p12.2 microdeletion include:

  • Developmental delays
  • Mild to moderate intellectual disability
  • Speech delays
  • Psychiatric and behavioral abnormalities including bipolar disorder, depression, and schizophrenia
  • Mild dysmorphic facial features without a consistent pattern
  • Congenital cardiac defects
  • Sleep disturbance
  • Epilepsy
  • A positive family history of learning disorders or psychiatric issues

Establishing the Diagnosis

The diagnosis of 16p12.2 microdeletion is established by demonstration of a 520-kb heterozygous deletion on chromosome 16p12.2 (see Table 1 and Molecular Genetics).

The recurrent 16p12.2 microdeletion involves the loss of one chromosomal segment harboring seven annotated genes or transcripts (see Molecular Genetics). This recurrent deletion is flanked by segmental duplications (defined as large [>1-kb] blocks of repeat sequences with >90% in sequence identity) that contain six additional genes (see Molecular Genetics). It is currently unknown how deletion of any of the genes causes the clinical findings of 16p12.2 microdeletion.

The 16p12.2 microdeletion can be detected by whole-genome or targeted deletion analysis that determines the copy number of sequences within the deleted region.

  • Genomic microarray technologies. Chromosome microarray analysis (CMA) using oligonucleotide arrays or SNP genotyping arrays can detect the common deletion in a proband. The ability to accurately determine the size of the deletion depends on the type of microarray used and the density of probes in the 16p12.2 region.
  • Targeted deletion analysis, including fluorescence in situ hybridization (FISH) and multiplex ligation-dependent probe amplification (MLPA), can be used if the deletion is suspected clinically and/or for confirmation of the deletion after genomic microarray analysis.

Table 1.

Summary of Molecular Genetic Testing Used in 16p12.2 Microdeletion

Test MethodPathogenic Variants DetectedProportion of Probands with a Pathogenic Variant Detectable by This Method
Deletion/duplication analysis 1Deletion of 520 kb in size 2~100% with appropriate probes 3
1.

Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

2.

Deletion of chromosome 16 from coordinates ~21,950,000-~22,470,000 (genome build UCSC hg19/NCBI37) (see Molecular Genetics and Nomenclature).

3.

Depending on the initial test that identifies the deletion, validation of the deletion by an independent method may be warranted. If high-density genomic microarray platforms have been used for the identification of the deletion, validation of the deletion may not be necessary, as it is unlikely that >50-100 adjacent targets show an abnormal copy number by chance.

Clinical Characteristics

Clinical Description

Due to the variable expressivity of microdeletion 16p12.2, this variant was not known prior to the use of chromosomal microarray testing in genetic diagnosis. The significant bias in ascertainment of children with intellectual disability and developmental delay [Girirajan et al 2010, Cooper et al 2011] and of individuals with schizophrenia [Rees et al 2014] undergoing clinical chromosomal microarray analysis makes it difficult to accurately associate specific phenotypes with the 16p12.2 microdeletion (Table 2).

Table 2.

Clinical Features in Probands with 16p12.2 Microdeletion

FindingFrequency%
Developmental delay19/2095%
Speech delay15/1788%
Craniofacial, skeletal features23/2688%
Growth retardation9/2241%
Microcephaly7/2232%
Congenital cardiac defect8/2433%
Epilepsy8/2532%
Psychiatric/behavioral disorders9/1656%
Hearing loss3/1817%
Hypotonia10/2245%
Sacral dimple or tethered cord4/2417%

de Jong et al [2010], Girirajan et al [2010], D'Alessandro et al [2014], Rai & Sharif [2015]
Some probands had additional genetic abnormalities identified that likely contributed to their phenotypes; frequencies therefore likely represent an ascertainment bias.

A study including 23 unrelated probands with 16p12.2 microdeletions from a (postnatal) clinical genetic testing cohort yielded the following phenotypic findings [Girirajan et al 2010]. Because of the nature of this clinic population, some of the phenotypes may reflect an ascertainment bias.

Developmental delay. In the report of Girirajan et al [2010], developmental delay ranging from mild to profound was present in all individuals with a 16p12.2 microdeletion. All individuals older than age 12 months showed speech delay; some remained nonverbal into childhood and adolescence. Motor milestones could also be affected, and many individuals were noted to have global delays.

In contrast, individuals with the microdeletion who were specifically ascertained for heart defects did not show delayed development [D'Alessandro et al 2014]. Similarly, normal early language development was described in the report of a one-year-old child with the microdeletion [Rai & Sharif 2015].

Cognitive development. In the report of Girirajan et al [2010], a spectrum of cognitive abilities has been described in individuals with a 16p12.2 microdeletion, ranging from normal in heterozygous parents to mild impairments to profoundly affected, nonverbal individuals. However, parents with the microdeletion were more likely to manifest learning disabilities than parents who did not have the microdeletion.

Dysmorphic features. While dysmorphic features are reported in a majority of individuals with a 16p12.2 microdeletion, no consistent pattern was evident [Girirajan et al 2010].

Growth. Approximately two fifths of pediatric probands had growth retardation; three were specifically noted to have short stature [Girirajan et al 2010].

Another individual with a 16p12.2 microdeletion had low birth weight and length [Rai & Sharif 2015].

Microcephaly was present in seven of 22 pediatric probands, including two who had otherwise normal growth parameters [de Jong et al 2010, Girirajan et al 2010, Rai & Sharif 2015].

Cardiac malformations. Microdeletions of 16p12.2 may be a risk factor for cardiac malformations. While not all individuals with these microdeletions have had echocardiography, eight children had cardiac defects, including hypoplastic left heart (found in 4, 2 of whom also had heterotaxy), ventricular septal defect, patent foramen ovale, absence of posterior pericardium, bicuspid aortic valve, patent ductus arteriosus, and tetralogy of Fallot [Girirajan et al 2010, D'Alessandro et al 2014]. However, 16p12.2 microdeletions are unlikely to be a major cause of left-sided cardiac lesions [D'Alessandro et al 2014].

Epilepsy. Approximately one third of probands with a 16p12.2 deletion experienced seizures and/or had abnormal findings on EEG. Seizure types included West syndrome, staring spells, epilepsy with myoclonus, and febrile seizures [Girirajan et al 2010].

Psychiatric and behavior problems. Psychiatric and/or behavioral problems were identified in more than half (9/16) of individuals with a 16p12.2 microdeletion who were assessed for these features. Autistic features or stereotypies were specifically noted in three individuals, poor attention was noted in three, and aggression was noted in two [Girirajan et al 2010].

Microdeletions of 16p12.2 have also been reported to be significantly enriched among individuals with schizophrenia, with an associated odds ratio of 2.72 (95% confidence interval, 1.48-5.02) relative to a control population [Rees et al 2014]. Additionally, one control identified to have a 16p12.2 microdeletion was retrospectively diagnosed with major depressive disorder, and parents with a 16p12.2 microdeletion were also significantly more likely to have mild learning disability or psychiatric issues such as depression or bipolar disorders than parents without the microdeletion [Girirajan et al 2010].

Other neurologic features. Hearing loss has been described in three individuals: unilateral in two and bilateral in one; sensorineural in two and unspecified in one [Girirajan et al 2010].

Hypotonia was seen in 10/22 individuals assessed for this feature [Girirajan et al 2010, Rai & Sharif 2015].

Either a sacral dimple or tethered cord was present in four of 24 individuals assessed [de Jong et al 2010, Girirajan et al 2010, D'Alessandro et al 2014, Rai & Sharif 2015].

Abnormal brain imaging was reported in five (63%) of eight individuals, with features including cerebellar and cerebral atrophy, decreased white matter, unspecified periventricular changes, and agenesis of the corpus callosum [Girirajan et al 2010].

One individual with a 16p12.2 microdeletion had postnatal onset of hydrocephalus due to cervicomedullary spinal stenosis [Rai & Sharif 2015], and an additional individual reportedly had congenital hydrocephalus without additional clinical details available [Girirajan et al 2010].

Other congenital anomalies. Aside from heart defects, other congenital anomalies have only occasionally been reported, and some of these may be attributable to other unknown genetic factors. Out of 26 reported probands with 16p12.2 microdeletions [de Jong et al 2010, Girirajan et al 2010, D'Alessandro et al 2014, Rai & Sharif 2015]:

  • Four children had absence of canine teeth with duplication of incisors bilaterally, pegged incisors, crowded teeth, and/or dental caries.
  • Three children had renal abnormalities (small kidneys, horseshoe kidney, or hydronephrosis).
  • Three males had genital anomalies, including chordee, hypospadias, and cryptorchidism [Girirajan et al 2010, de Jong et al 2010].
  • Two had cleft palate, one with cleft lip.
  • Two had clubfoot or bowed legs.
  • Single individuals have been reported with craniosynostosis, inguinal hernia, and tracheal agenesis, although the last was in an individual who had an additional rare copy number variant [Girirajan et al 2010, de Jong et al 2010].

Genotype-Phenotype Correlations

Probands with 16p12.2 microdeletion manifesting abnormal phenotypes are significantly more likely than controls to have a second rare, unrelated, large (>500 kb) copy number variant (CNV) [Girirajan et al 2010, Girirajan et al 2012]. Such individuals had distinct or more severe phenotypes compared to the classic phenotypes associated with the known second pathogenic CNV, suggesting that the 16p12.2 microdeletion is an independent risk factor for neurodevelopmental phenotypes in association with other large, pathogenic CNVs [Girirajan et al 2010].

Penetrance

Penetrance for 16p12.2 microdeletions is incomplete.

The 16p12.2 microdeletion was documented to be enriched in a population undergoing clinical chromosomal microarray analysis [Girirajan et al 2010, Cooper et al 2011] and among individuals with schizophrenia [Rees et al 2014]. Further studies also identified the microdeletion in apparently healthy parents of probands and controls. On further follow up, parents with the microdeletion were found to be more likely to have clinical findings such as seizures, mild intellectual disability, and/or psychiatric issues suggesting that the 16p12.2 microdeletion is a risk factor for abnormal neurodevelopmental phenotypes with reduced penetrance and variable expressivity.

Based on data from children undergoing clinical chromosome microarray analysis and adult controls, estimates for intellectual disability/developmental delay and/or congenital malformations in those with a 16p12.2 microdeletion were 12.3% (95% confidence interval, 7.91%-18.8%) [Rosenfeld et al 2013] and 13% (95% confidence interval, 5.7%-30%) [Kirov et al 2014].

Kirov et al [2014] estimated the penetrance of schizophrenia among individuals with a 16p12.2 microdeletion to be 3.1% (95% confidence interval, 1.2%-8.3%).

In addition, individuals with a 16p12.2 microdeletion are more likely to have a family history of neuropsychiatric phenotypes suggesting segregation of neuropsychiatric risk factors other than 16p12.2 microdeletion. Of note, ten (~25%) of 42 probands with 16p12.2 microdeletion also had another large (>500 kb) CNV elsewhere in the genome. The “second hit” was frequently de novo or transmitted from the parent who did not have the 16p12.2 microdeletion. These observations suggest that the microdeletion confers risk for neuropsychiatric features and that the penetrance and expressivity of the deletion-associated phenotype depends on the presence of a second large CNV or potentially other genetic modifiers elsewhere in the genome.

The proportion of males is higher among all individuals with a CNV associated with reduced penetrance and variable expressivity (like a 16p12.2 microdeletion) as compared to those with syndromic CNVs (like Smith-Magenis syndrome, where the proportion of males is ~50%), suggesting that penetrance may be higher in males than females [Girirajan et al 2012, Jacquemont et al 2014].

Anticipation

While almost all reports describe identification of the 16p12.2 microdeletion in individuals who are more severely affected than a parent with the microdeletion, this is more likely to reflect an ascertainment bias than genetic anticipation. Changes in the size of a 16p12.2 microdeletion on transmission from one generation to the next have not been described [Girirajan et al 2010].

Nomenclature

The chromosomal location of the microdeletion originally described at 16p12.1 (from coordinates ~21,850,000-~22,370,000, genome build hg18/NCB136) has changed to 16p12.2 (from coordinates ~21,950,000-~22,470,000, genome build hg19/GRCh37). Clinical reports and descriptions now use the 16p12.2 location/nomenclature.

Prevalence

The estimated frequency of 16p12.2 microdeletion – on the order of 0.19% of individuals undergoing clinical microarray-based testing [Rosenfeld et al 2013] – is similar to that of Smith-Magenis syndrome, suggesting that Smith-Magenis syndrome and 16p12.2 microdeletion associated with an abnormal phenotype may have a similar incidence of approximately 1:15,000 live births [Girirajan et al 2010].

However, this estimate does not account for healthy or mildly affected individuals who are heterozygous for the microdeletion.

Differential Diagnosis

The differential diagnosis for 16p12.2 microdeletion is broad, including many causes of developmental delays and/or behavior abnormalities, which are frequently nonsyndromic and not associated with characteristic distinguishing features and, thus, require chromosomal microarray analysis for diagnosis.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with the 16p12.2 microdeletion, the following evaluations are recommended:

  • Clinical genetics consultation
  • Measurement of height and weight
  • Broad review of all organ systems
  • Developmental assessment with cognitive and behavioral testing
  • To consider:
    • Consultation with a neurologist and EEG testing if history suggests the possibility of seizures
    • Evaluation and echocardiogram by a cardiologist

Treatment of Manifestations

Because manifestations of 16p12.2 microdeletion are variable, treatment should be targeted to the specific problems identified. Early diagnosis and treatment facilitate the best outcome. Referral to other appropriate medical specialists is recommended based on specific signs and symptoms. Specialists may include a developmental/behavioral pediatrician, pediatric neurologist, and/or medical geneticist.

Developmental and cognitive delays. Initiate developmental therapies promptly when indicated. Cognitive testing in older children may help identify any specific learning or cognitive disabilities that could be addressed by therapies or specialized education plans.

Cardiac malformations. Individuals with 16p12.2 microdeletion and cardiac malformations should have standard treatment for the malformation, including surgical correction and prophylactic antibiotic treatments as indicated.

Epilepsy. A history suggestive of possible seizure activity should prompt referral to a neurologist for additional testing, including brain imaging and EEG, and consideration of medical intervention.

Psychiatric and/or behavior problems. In individuals of any age, signs of psychiatric or behavioral problems should prompt referral to specialists, including developmental/behavioral pediatricians, psychologists, or psychiatrists, so that formal assessments may be performed and appropriate interventions (medical, social, behavioral, and/or educational) may be made.

Hearing loss. Standard treatment should be provided for hearing loss. See Hereditary Hearing Loss and Deafness.

Other malformations. Standard treatment should be provided for any other malformations, including oro-facial clefting and renal, genitourinary, or dental anomalies.

Surveillance

Periodic:

  • Developmental evaluations because of the increased incidence of developmental delay, intellectual disability, autism spectrum disorders, and other behavioral features
  • Monitoring of cardiac, renal, urologic, and/or dental abnormalities, as needed
  • Reevaluation by a medical geneticist who can apprise the family of new recommendations for monitoring for medical or mental health concerns.

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

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

The 16p12.2 microdeletion is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • The majority (~95%) of individuals with a 16p12.2 microdeletion have inherited the microdeletion from a parent (who may or may not have clinical features of 16p12.2 microdeletion).
  • A single, apparently de novo 16p12.2 microdeletion has been described (for a de novo rate of 3.6%) [Rosenfeld et al 2013]. However, additional testing to confirm parentage was not performed.
  • If a 16p12.2 microdeletion cannot be detected in either parent, it is possible that a parent of a proband has:
    • Germline mosaicism or low-level somatic mosaicism that also includes the germline (see Note)

      OR
    • A balanced chromosomal rearrangement involving the 16p12.2 region.
      Note: Such a balanced chromosomal rearrangement would not be detected by standard chromosomal microarray analysis (CMA) but could be identified by FISH analysis.
  • The family history of some individuals diagnosed with a 16p12.2 microdeletion may appear to be negative because of reduced penetrance and variable expressivity. Therefore, an apparently negative family history cannot be confirmed unless appropriate molecular genetic testing has been performed on the parents of the proband.

Note: Germline mosaicism, somatic mosaicism, and balanced chromosomal rearrangements involving the 16p12.2 region have not been reported with 16p12.2 microdeletions.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the parents.
  • If a parent is heterozygous for the 16p12.2 microdeletion, the risk to the sibs of inheriting the microdeletion is 50%; however, the risk that sibs would be affected is less than 50% because of reduced penetrance for the microdeletion.
    • The presence of neuropsychiatric phenotypes in a parent with the microdeletion may indicate higher penetrance within a family; however, it is not possible to reliably predict the expressivity of 16p12.2 microdeletion in sibs of a proband. (See Penetrance.)

Offspring of a proband

  • Each child of an individual with a 16p12.2 microdeletion has a 50% chance of inheriting the deletion.
  • The risk to offspring of being affected is less than 50% because of reduced penetrance. (See Penetrance.)

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the 16p12.2 microdeletion, his or her family members may also have the microdeletion.

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 individuals who are at risk of having a child with the 16p12.2 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

If a 16p12.2 microdeletion has been identified in an affected family member, prenatal testing and preimplantation genetic diagnosis for a pregnancy at increased risk for a 16p12.2 microdeletion are possible options. However, it is not possible to reliably predict phenotype based on the laboratory finding of a 16p12.2 microdeletion.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

No specific resources for 16p12.2 Microdeletion have been identified by GeneReviews staff.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

16p12.2 Microdeletion: Genes and Databases

GeneChromosome LocusProtein
Not applicable16p12​.2Not applicable

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for 16p12.2 Microdeletion (View All in OMIM)

136570CHROMOSOME 16p12.1 DELETION SYNDROME, 520-KB

Molecular Genetic Pathogenesis

The 520-kb microdeletion at chromosome 16p12.2 (coordinates ~21,950,000-~22,470,000, genome build UCSC hg19/GRCh37) results in the deletion of seven genes: UQCRC2, PDZD9, C16ORF52, VWA3A, EEF2K, POLR3E, and CDR2 (RefSeq genes, UCSC hg19/GRCh37). How hemizygosity for one or more of these genes results in the clinical manifestations of the deletion is unknown. Of note, the deletion is flanked by segmental duplications (defined as large [>1-kb] blocks of repeat sequences with >90% in sequence identity) that contain six additional genes.

The 16p12.2 microdeletion is mediated by recombination between flanking 68-kb low-copy segmental duplications with 99.5% sequence identity [Antonacci et al 2010, Girirajan et al 2010]. Based on the number and orientation of segmental duplications, two common haplotypes have been identified in the general population [Antonacci et al 2010]. Haplotype S2 has the 68-kb segmental duplications in direct orientation flanking the 16p12.2 microdeletion region, suggesting that it would predispose to the recurrent 16p12.2 microdeletion. Consistent with this hypothesis, the S2 haplotype is enriched among individuals with a 16p12.2 microdeletion. The population frequency of the S2 haplotype varies among those with African (97.5%), European (83.1%), and Asian (71.6%) ancestries. Therefore, African and European populations likely have a higher risk for 16p12.2 microdeletions than Asian populations [Antonacci et al 2010].

While the pericentromeric region of chromosome 16 has many segmental duplications that can mediate recurrent microdeletions, this 16p12.2 microdeletion specifically refers to the deletion of the segment from coordinates ~21,850,000-~22,370,000 (16p12.1, UCSC hg18/NCBI36) or ~21,950,000-~22,470,000 (UCSC hg19/GRCh37).

References

Literature Cited

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  15. Jacquemont S, Coe BP, Hersch M, Duyzend MH, Krumm N, Bergmann S, Beckmann JS, Rosenfeld JA, Eichler EE. A higher mutational burden in females supports a "female protective model" in neurodevelopmental disorders. Am J Hum Genet. 2014;94:415–25. [PMC free article: PMC3951938] [PubMed: 24581740]
  16. Kirov G, Rees E, Walters JT, Escott-Price V, Georgieva L, Richards AL, Chambert KD, Davies G, Legge SE, Moran JL, McCarroll SA, O'Donovan MC, Owen MJ. The penetrance of copy number variations for schizophrenia and developmental delay. Biol Psychiatry. 2014;75:378–85. [PMC free article: PMC4229045] [PubMed: 23992924]
  17. Okamoto N, Fujii T, Tanaka J, Saito K, Matsui T, Harada N. A clinical study of patients with pericentromeric deletion and duplication within 16p12.2-p11.2. Am J Med Genet A. 2014;164A:213–9. [PubMed: 24259393]
  18. Rai B, Sharif F. Cervicomedullary Spinal Stenosis and Ventriculomegaly in a Child With Developmental Delay due to Chromosome 16p12.1 Microdeletion Syndrome. J Child Neurol. 2015;30:394–6. [PubMed: 24813870]
  19. Rees E, Walters JT, Chambert KD, O'Dushlaine C, Szatkiewicz J, Richards AL, Georgieva L, Mahoney-Davies G, Legge SE, Moran JL, Genovese G, Levinson D, Morris DW, Cormican P, Kendler KS, O'Neill FA, Riley B, Gill M, Corvin A, Sklar P, Hultman C, Pato C, Pato M, Sullivan PF, Gejman PV, McCarroll SA, O'Donovan MC, Owen MJ, Kirov G. CNV analysis in a large schizophrenia sample implicates deletions at 16p12.1 and SLC1A1 and duplications at 1p36.33 and CGNL1. Hum Mol Genet. 2014;23:1669–76. [PMC free article: PMC3929090] [PubMed: 24163246]
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Suggested Reading

  1. International Schizophrenia Consortium. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature. 2008;455:237–41. [PMC free article: PMC3912847] [PubMed: 18668038]

Chapter Notes

Author Notes

Santhosh Girirajan’s Laboratory

I am interested in understanding the causes and consequences of genome structure and function as related to human neurodevelopmental disorders such as intellectual disability and developmental delay, autism, schizophrenia, and epilepsy. My graduate work on Smith-Magenis syndrome (SMS) trained me in understanding how all individuals carrying a deletion encompassing the retinoic acid induced 1 gene (RAI1) have invariable phenotypes [Girirajan et al 2005, Girirajan et al 2006]. Further, analysis of mouse models altering Rai1 gene dosage confirmed the role of RAI1 in SMS [Girirajan et al 2008, Girirajan & Elsea 2009a, Girirajan & Elsea 2009b]. As a postdoctoral fellow in Evan Eichler’s lab, I was involved in identifying and studying another class of CNVs where the causal gene is not known and individuals carrying the same deletion or duplication manifest a wide variety of phenotypes. I was able to demonstrate that a second variant in addition to the primary genomic lesion can explain the observed phenotypic variability. Originally described for 16p12.1 deletion [Girirajan et al 2010], the “two-hit” model was successfully replicated to explain the phenotypic heterogeneity in other recently identified CNVs such as 16p11.2 deletion, 15q13.3 deletion,17q12 deletion, 15q11.2 deletion, and 1q21.1 deletion [Girirajan et al 2012].

Revision History

  • 26 February 2015 (me) Review posted live
  • 9 September 2014 (sg) Original submission
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