Clinical characteristics.

The 1q21.1 recurrent deletion itself does not lead to a clinically recognizable syndrome, as some persons with the deletion have no obvious clinical findings. Others have variable findings that most commonly include mildly dysmorphic but nonspecific facial features (>75%), mild intellectual disability or learning disabilities (25%), microcephaly (43%), and eye abnormalities (26%). Other findings can include cardiac defects, genitourinary anomalies, skeletal malformations, joint laxity, and seizures (~23%). Psychiatric and behavioral abnormalities can include autism spectrum disorder, attention-deficit/hyperactivity disorder, and sleep disturbances. Sensorineural hearing loss and recurrent infections /otitis media are rare.

Diagnosis/testing.

The diagnosis of the 1q21.1 recurrent deletion is established by the detection of the recurrent distal heterozygous deletion between BP3 and BP4 at the approximate position of chr1:147105904-147917509 in the reference genome (NCBI Build 38).

Management.

Treatment of manifestations: Feeding therapy to address poor growth, with a low threshold for a clinical feeding evaluation and/or radiographic swallowing study when there are clinical signs or symptoms of dysphagia. Standard treatment for gastroparesis, constipation, gastroesophageal reflux disease, developmental delay / intellectual disability, eye anomalies/refractive error, congenital heart disease, epilepsy, tremors/tics, hernia, cryptorchidism, skeletal anomalies, and hearing loss.

Surveillance: At each visit: measure growth parameters; monitor for constipation; assessment for anxiety, ADHD, and behavioral problems; monitor for developmental progress and educational needs; monitor those with seizures as clinically indicated; assess for new manifestations, such as seizures, tremors, or tics; and assess motility and self-help skills. At least annually or as clinically indicated: ophthalmology evaluation and audiology evaluation.

Genetic counseling.

The 1q21.1 recurrent deletion is inherited in an autosomal dominant manner. Between 18% and 35% of deletions occur de novo. The deletion can be inherited from either parent; a parent with the deletion may show a normal phenotype or an abnormal phenotype that is similar to but usually less severe than that of the parent's child. Each child of an individual with the 1q21.1 recurrent deletion has a 50% chance of inheriting the deletion; it is not possible to predict the phenotype in offspring who inherit the deletion. Recurrence risk for future pregnancies for parents who do not have the deletion is low (probably <1%) but greater than that of the general population because of the possibility of germline mosaicism.

Suggestive Findings

The 1q21.1 recurrent deletion should be considered in probands with the following clinical features:

• Hypotonia
• Developmental delays
• Intellectual disability (ID), typically in the mild-to-moderate range, although not all individuals with this deletion have ID
• Microcephaly
• Poor growth
• Neurobehavioral/psychiatric manifestations, such as behavioral outbursts, attention-deficit/hyperactivity disorder, aggression, sleep disturbances, or autism spectrum disorder
• Seizures
• Ophthalmologic involvement, such as strabismus or nystagmus
• Hearing impairment
• Joint laxity
• Mild but nonspecific dysmorphic facial features (See Clinical Description.)

Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Because not all individuals with this deletion will have discernable clinical features, absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of the 1q21.1 recurrent deletion is established by detection of the recurrent distal 0.8-Mb heterozygous deletion at the approximate position of chr1:147105904-147917509 in the reference genome (NCBI Build 38).

Note: (1) The phenotype of significantly larger or smaller deletions within this region may be clinically distinct from the 1q21.1 recurrent deletion (see Molecular Genetics). (2) For features of the reciprocal 1q21.1 duplication (defined as between BP3-BP4), see Genetically Related Disorders.

Although several genes of interest (PRKAB2, FMO5, CHD1L, BCL9, ACP6, GJA5, GJA8) are within the distal 0.8-Mb recurrent deletion [Yoon & Mao 2021], no single gene has been identified to be causative of the overall phenotype of this recurrent deletion syndrome (see Molecular Genetics for genes of interest in the deleted region).

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) The 1q21.1 recurrent deletion cannot be identified by routine analysis of G-banded chromosomes or other conventional cytogenetic banding techniques. (2) Most individuals with the 1q21.1 recurrent deletion are identified by CMA performed in the context of developmental delay, intellectual disability, or autism spectrum disorders. (3) Prior to 2008 many CMA platforms did not include coverage of the 1q21.1 region and thus may not have detected this deletion.

Clinical Description

Individuals with the 1q21.1 recurrent deletion (BP3-BP4) have a wide range of clinical manifestations, ranging from unaffected to severely affected. The most common findings include developmental delay and mild but nonspecific dysmorphic facies. There is not a clinically recognizable syndrome, as a subset of persons with the deletion do not have obvious clinical findings.

Clinical information from reports involving 102 probands with the 1q21.1 recurrent deletion is summarized in Table 2 [Brunetti-Pierri et al 2008, Mefford et al 2008, Bernier et al 2016, Edwards et al 2021, Bourgois et al 2023].

Facial features. Dysmorphic craniofacial features are a common finding but are highly variable and therefore not easily recognizable nor characteristic. The facial features may include frontal bossing; thin eyebrows; deep-set eyes; epicanthal folds; prominent, large, and/or wide nasal bridge with bulbous tip; long philtrum; and highly arched palate.

Growth. Microcephaly is described in 43% of individuals with the 1q21.1 recurrent deletion. This is more common in females than males. Short stature and poor growth may also be seen. While approximately 19% of individuals were described as having dysphagia, a definite etiology for poor growth (such as growth hormone deficiency) has not been determined [Edwards et al 2021] (see also Gastrointestinal issues in the following text).

Developmental delay (DD) and intellectual disability (ID). The majority of individuals with the 1q21.1 recurrent deletion have developmental delay.

• Most delays are mild and may involve specific areas, particularly gross motor delay, or be global, involving all areas of development.
• Some may also have generalized learning disabilities throughout life.
• Mild intellectual disability and learning disabilities are seen in approximately 25% of affected individuals.

Ophthalmologic involvement is present in about one third of individuals and may include strabismus, nystagmus, nasolacrimal duct obstruction, chorioretinal and iris colobomas, microphthalmia, hypermetropia, Duane anomaly, and various types of cataracts (e.g., congenital, nuclear pulverulent) [Edwards et al 2021].

Neurobehavioral/psychiatric manifestations. Psychiatric and behavioral abnormalities that may be present include autism spectrum disorders, attention-deficit/hyperactivity disorder (ADHD), anxiety and mood disorders, sleep disturbances, and self-injurious behaviors. In addition, distal 1q21.1 deletions 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].

Cardiac anomalies. Several reported individuals with the 1q21.1 recurrent deletion have cardiac defects [Digilio et al 2013, Edwards et al 2021], which may include:

• Patent ductus arteriosus
• Truncus arteriosus
• Ventricular and atrial septal defects
• Tetralogy of Fallot
• Bicuspid aortic valve
• Dilatation of ascending aorta, with no further information on whether this is progressive or static
• Aortic insufficiency
• Coarctation of the aorta
• Interrupted aortic arch
• Supravalvular aortic stenosis
• Anomalous origin of the right coronary artery
• Pulmonary valve stenosis
• Transposition of the great vessels
• Rhythm abnormalities (sinus bradycardia, prolonged QT interval). Of note, one individual with long QT syndrome was also found to have a pathogenic KCNH2 variant.

Females are more likely to have a cardiac anomaly.

Neurologic. 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 23% of individuals and often begin during the first year of life.
• Brain malformations that have been described range from structural anomalies (including agenesis of the corpus callosum) to migrational anomalies. Hydrocephalus has also been reported.

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

Gastrointestinal issues include chronic constipation, dysphagia, gastroesophageal reflux, and poor gastric emptying/gastroparesis. Some affected individuals required G-tube for feeding difficulty [Edwards et al 2021].

Skeletal malformations are variable and include:

• Craniosynostosis (one report of metopic synostosis specifically)
• Scoliosis, ranging from mild to severe (requiring spinal hardware)
• 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
• Polydactyly of the hands or feet

Hearing impairment. Sensorineural hearing loss has been reported in at least five individuals, with an additional six individuals having mild-to-profound hearing loss, though conductive/sensorineural/mixed is not specified.

Recurrent infections have been reported in a minority of affected individuals and may include frequent otitis media [Bourgois et al 2023].

Genotype-Phenotype Correlations

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

Penetrance

Little information is available regarding penetrance of the 1q21.1 recurrent deletion. Similar to several other recurrent deletions (e.g., 16p11.2, 15q13.3), the 1q21.1 recurrent deletion 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 deletion 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 2016; Authors, personal observation]. This suggests that the 1q21.1 recurrent deletion has reduced penetrance and variable expressivity.

Prevalence

The frequency of the 1q21.1 recurrent deletion is approximately 0.2% (46/22,563) of individuals with developmental delays, intellectual disabilities, and/or congenital anomalies evaluated by chromosomal microarray [Brunetti-Pierri et al 2008, Mefford et al 2008, Rosenfeld et al 2013]. The estimated prevalence for 1q21.1 deletions in the general population is 0.01% (1/6,882) [Gillentine et al 2018].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with the 1q21.1 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

There is no cure for the 1q21.1 recurrent deletion. Supportive care to improve quality of life, maximize function, and reduce complications is recommended (see Table 4).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

Evaluation of Relatives at Risk

Using genomic testing that will detect the 1q21.1 recurrent deletion 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.

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 deletion.

Note: (1) Targeted deletion testing is not appropriate for an individual in whom the 1q21.1 recurrent deletion was not detected by chromosomal microarray designed to target this region. (2) It is not possible to size the deletion routinely by use of targeted methods.

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 deletion is inherited in an autosomal dominant manner.

The recurrent deletion can be inherited from either parent, and it does not appear that the phenotypic severity varies with the parent of origin.

Risk to Family Members

Parents of a proband

• Many individuals with the 1q21.1 recurrent deletion inherited the deletion from a parent. A parent with the recurrent deletion 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 deletion is inherited, the parent has a normal phenotype.
  • 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 deletion.
  • In another study [Brunetti-Pierri et al 2008], 82% (9/11) of the probands for whom parental testing was possible had inherited the deletion.
• Edwards et al [2021] identified a de novo rate of 35% (8/23) in probands for whom parental testing data were available.
• Genomic testing that will detect the 1q21.1 recurrent deletion present in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the 1q21.1 recurrent deletion identified in the proband is not identified in either confirmed biological parent, the following possibilities should be considered:
  • The proband has a de novo deletion.
  • The proband inherited a deletion from a parent with germline (or somatic and germline) mosaicism. 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.
• The family history of some individuals diagnosed with the 1q21.1 recurrent deletion may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the 1q21.1 recurrent deletion.

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

• If one of the parents has the 1q21.1 recurrent deletion, the risk to each sib of inheriting the deletion is 50%. Because studies suggest that the 1q21.1 recurrent deletion is associated with variable expressivity and reduced penetrance, it is not possible to reliably predict the phenotype in a sib who inherits the deletion.
• If the 1q21.1 recurrent deletion identified in the proband cannot be detected in either of the parents, the recurrence risk to sibs is low (<1%) but greater than that of the general population because of the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with the 1q21.1 recurrent deletion has a 50% chance of inheriting the deletion; it is not possible to predict the phenotype in offspring who inherit 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 1q21.1 recurrent deletion, the parent's family members may also have the deletion.

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.
• 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 deletion.

Prenatal Testing and Preimplantation Genetic Testing

Pregnancies known to be at increased risk for the 1q21.1 recurrent deletion. Once a 1q21.1 recurrent deletion has been identified in a family member, prenatal and preimplantation genetic testing are possible.

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

Note: Regardless of whether a pregnancy is known or not known to be at increased risk for the 1q21.1 recurrent deletion, the prenatal finding of a 1q21.1 recurrent deletion cannot be used to predict the phenotype (see Penetrance).

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

Author Notes

Baylor Genetics is conducting data collection on individuals with 1q21.1 distal deletions. Interested parties should contact ude.mcb@emonegnoisicerp.

Author History

Rose Guo, DO (2024-present)
Chad R Haldeman-Englert, MD (2011-present)
Tamison Jewett, MD; Wake Forest University School of Medicine (2011-2024)

Revision History

• 1 February 2024 (ma) Comprehensive update posted live
• 12 November 2015 (me) Comprehensive update posted live
• 24 February 2011 (me) Review posted live
• 30 November 2010 (che) Original submission

Literature Cited

• Bernier R, Steinman KJ, Reilly B, Wallace AS, Sherr EH, Pojman N, Mefford HC, Gerdts J, Earl R, Hanson E, Goin-Kochel RP, Berry L, Kanne S, Snyder LG, Spence S, Ramocki MB, Evans DW, Spiro JE, Martin CL, Ledbetter DH, Chung WK; Simons VIP Consortium. Clinical phenotype of the recurrent 1q21.1 copy-number variant. Genet Med. 2016;18:341-9. [PMC free article: PMC7263044] [PubMed: 26066539]
• Bourgois A, Bizaoui V, Colson C, Vincent-Devulder A, Molin A, Gérard M, Gruchy N. Phenotypic and genotypic characterization of 1q21.1 copy number variants: a report of 34 new individuals and literature review. Am J Med Genet A. 2023. Epub ahead of print. [PubMed: 37881147]
• Brunetti-Pierri N, Berg JS, Scaglia F, Belmont J, Bacino CA, Sahoo T, Lalani SR, Graham B, Lee B, Shinawi M, Shen J, Kang SH, Pursley A, Lotze T, Kennedy G, Lansky-Shafer S, Weaver C, Roeder ER, Grebe TA, Arnold GL, Hutchison T, Reimschisel T, Amato S, Geragthy MT, Innis JW, Obersztyn E, Nowakowska B, Rosengren SS, Bader PI, Grange DK, Naqvi S, Garnica AD, Bernes SM, Fong CT, Summers A, Walters WD, Lupski JR, Stankiewicz P, Cheung SW, Patel A. Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities. Nat Genet. 2008;40:1466–71. [PMC free article: PMC2680128] [PubMed: 19029900]
• Ceroni F, Aguilera-Garcia D, Chassaing N, Bax DA, Blanco-Kelly F, Ramos P, Tarilonte M, Villaverde C, da Silva LRJ, Ballesta-Martínez MJ, Sanchez-Soler MJ, Holt RJ, Cooper-Charles L, Bruty J, Wallis Y, McMullan D, Hoffman J, Bunyan D, Stewart A, Stewart H, Lachlan K; DDD Study; Fryer A, McKay V, Roume J, Dureau P, Saggar A, Griffiths M, Calvas P, Ayuso C, Corton M, Ragge NK. New GJA8 variants and phenotypes highlight its critical role in a broad spectrum of eye anomalies. Hum Genet. 2019;138:1027-42. [PubMed: 29464339]
• Chapman G, Alsaqati M, Lunn S, Singh T, Linden SC, Linden DEJ, van den Bree MBM, Ziller M, Owen MJ, Hall J, Harwood AJ, Syed YA. Using induced pluripotent stem cells to investigate human neuronal phenotypes in 1q21.1 deletion and duplication syndrome. Mol Psychiatry. 2022;27:819-30. [PMC free article: PMC9054650] [PubMed: 34112971]
• Chen CP, Huang JP, Chen YY, Chern SR, Wu PS, Chen SW, Wang W, Lee CC. Detection of a familial 1q21.1 microdeletion and concomitant CHD1L mutation in a fetus with oligohydramnios and bilateral renal dysplasia on prenatal ultrasound. Taiwan J Obstet Gynecol. 2019;58:859-63. [PubMed: 31759543]
• Chen MJ, Wei SY, Yang WS, Wu TT, Li HY, Ho HN, Yang YS, Chen PL. Concurrent exome-targeted next-generation sequencing and single nucleotide polymorphism array to identify the causative genetic aberrations of isolated Mayer-Rokitansky-Küster-Hauser syndrome. Hum Reprod. 2015;30:1732–42. [PubMed: 25924657]
• Christiansen J, Dyck JD, Elyas BG, Lilley M, Bamforth JS, Hicks M, Sprysak KA, Tomaszewski R, Haase SM, Vicen-Wyhony LM, Somerville MJ. Chromosome 1q21.1 contiguous gene deletion is associated with congenital heart disease. Circ Res. 2004;94:1429–35. [PubMed: 15117819]
• Digilio MC, Bernardini L, Consoli F, Lepri FR, Giuffrida MG, Baban A, Surace C, Ferese R, Angioni A, Novelli A, Marino B, De Luca A, Dallapiccola B. Congenital heart defects in recurrent reciprocal 1q21.1 deletion and duplication syndromes: rare association with pulmonary valve stenosis. Eur J Med Genet. 2013;56:144–9. [PubMed: 23270675]
• Edwards SD, Schulze KV, Rosenfeld JA, Westerfield LE, Gerard A, Yuan B, Grigorenko EL, Posey JE, Bi W, Liu P. Clinical characterization of individuals with the distal 1q21.1 microdeletion. Am J Med Genet A. 2021;185:1388-98. [PubMed: 33576134]
• Emanuel BS, Shaikh TH. Segmental duplications: an "expanding" role in genomic instability and disease. Nat Rev Genet. 2001;2:791–800. [PubMed: 11584295]
• Gillentine MA, Lupo PJ, Stankiewicz P, Schaaf, CP. An estimation of the prevalence of genomic disorders using chromosomal microarray data. J Hum Genet. 2018;63:795-801. [PMC free article: PMC6019170] [PubMed: 29691480]
• Girirajan S, Dennis MY, Baker C, Malig M, Coe BP, Campbell CD, Mark K, Vu TH, Alkan C, Cheng Z, Biesecker LG, Bernier R, Eichler EE. Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder. Am J Hum Genet. 2013;92:221-37. [PMC free article: PMC3567267] [PubMed: 23375656]
• Gollob MH, Jones DL, Krahn AD, Danis L, Gong X-Q, Shao Q, Liu X, Veinot JP, Tang ASL, Stewart AFR, Tesson F, Klein GJ, Yee R, Skanes AC, Guiraudon GM, Ebihara L, Bai D. Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation. New Eng J Med. 2006;354:2677–88. [PubMed: 16790700]
• Guida V, Ferese R, Rocchetti M, Bonetti M, Sarkozy A, Cecchetti S, Gelmetti V, Lepri F, Copetti M, Lamorte G, Cristina Digilio M, Marino B, Zaza A, den Hertog J, Dallapiccola B, De Luca A. A variant in the carboxyl-terminus of connexin 40 alters GAP junctions and increases risk for tetralogy of Fallot. Eur J Hum Genet. 2013;21:69–75. [PMC free article: PMC3533258] [PubMed: 22713807]
• Harvard C, Strong E, Mercier E, Colnaghi R, Alcantara D, Chow E, Martell S, Tyson C, Hrynchak M, McGillivray B, Hamilton S, Marles S, Mhanni A, Dawson AJ, Pavlidis P, Qiao Y, Holden JJ, Lewis SM, O'Driscoll M, Rajcan-Separovic E. Understanding the impact of 1q21.1 copy number variant. Orphanet J Rare Dis. 2011;6:54. [PMC free article: PMC3180300] [PubMed: 21824431]
• Huang X, Xiao X, Jia X, Li S, Li M, Guo X, Liu X. Zhang Q1. Mutation analysis of the genes associated with anterior segment dysgenesis, microcornea and microphthalmia in 257 patients with glaucoma. Int J Mol Med. 2015;36:1111–7. [PubMed: 26310487]
• Hwang DY, Dworschak GC, Kohl S, Saisawat P, Vivante A, Hilger AC, Reutter HM, Soliman NA, Bogdanovic R, Kehinde EO, Tasic V, Hildebrandt F. Mutations in 12 known dominant disease-causing genes clarify many congenital anomalies of the kidney and urinary tract. Kidney Int. 2014;85:1429–33. [PMC free article: PMC4040148] [PubMed: 24429398]
• International Schizophrenia Consortium. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature. 2008;455:237–41. [PMC free article: PMC3912847] [PubMed: 18668038]
• Li J, Zhou G, Ji W, Feng G, Zhao Q, Liu J, Li T, Li Y, Chen P, Zeng Z, Wang T, Hu Z, Zheng L, Wang Y, Shen Y, He L, Shi Y. Common variants in the BCL9 gene conferring risk of schizophrenia. Arch Gen Psychiatry. 2011;68:232-40. [PubMed: 21383261]
• Lupski JR, Stankiewicz P. Genomic disorders: molecular mechanisms for rearrangements and conveyed phenotypes. PLoS Genet. 2005;1:e49. [PMC free article: PMC1352149] [PubMed: 16444292]
• Mackay DS, Bennett TM, Culican SM, Shiels A. Exome sequencing identifies novel and recurrent mutations in GJA8 and CRYGD associated with inherited cataract. Hum Genomics. 2014;8:19. [PMC free article: PMC4240822] [PubMed: 25403472]
• Mefford HC, Sharp AJ, Baker C, Itsara A, Jiang Z, Buysse K, Huang S, Maloney VK, Crolla JA, Baralle D, Collins A, Mercer C, Norga K, de Ravel T, Devriendt K, Bongers EM, de Leeuw N, Reardon W, Gimelli S, Bena F, Hennekam RC, Male A, Gaunt L, Clayton-Smith J, Simonic I, Park SM, Mehta SG, Nik-Zainal S, Woods CG, Firth HV, Parkin G, Fichera M, Reitano S, Lo Giudice M, Li KE, Casuga I, Broomer A, Conrad B, Schwerzmann M, Raber L, Gallati S, Striano P, Coppola A, Tolmie JL, Tobias ES, Lilley C, Armengol L, Spysschaert Y, Verloo P, De Coene A, Goossens L, Mortier G, Speleman F, van Binsbergen E, Nelen MR, Hochstenbach R, Poot M, Gallagher L, Gill M, McClellan J, King MC, Regan R, Skinner C, Stevenson RE, Antonarakis SE, Chen C, Estivill X, Menten B, Gimelli G, Gribble S, Schwartz S, Sutcliffe JS, Walsh T, Knight SJ, Sebat J, Romano C, Schwartz CE, Veltman JA, de Vries BB, Vermeesch JR, Barber JC, Willatt L, Tassabehji M, Eichler EE. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N Engl J Med. 2008;359:1685–99. [PMC free article: PMC2703742] [PubMed: 18784092]
• Nagy S, Maurer GW, Hentze JL, Rose M, Werge TM, Rewitz K. AMPK signaling linked to the schizophrenia-associated 1q21.1 deletion is required for neuronal and sleep maintenance. PLoS Genet. 2018;14:e1007623. [PMC free article: PMC6317821] [PubMed: 30566533]
• Nielsen J, Fejgin K, Sotty F, Nielsen V, Mørk A, Christoffersen CT, Yavich L, Lauridsen JB, Clausen D, Larsen PH, Egebjerg J, Werge TM, Kallunki P, Christensen KV, Didriksen M. A mouse model of the schizophrenia-associated 1q21.1 microdeletion syndrome exhibits altered mesolimbic dopamine transmission. Transl Psychiatry. 2017;7:1261. [PMC free article: PMC5802512] [PubMed: 29187755]
• Prokudin I, Simons C, Grigg JR, Storen R, Kumar V, Phua ZY, Smith J, Flaherty M, Davila S, Jamieson RV. Exome sequencing in developmental eye disease leads to identification of causal variants in GJA8, CRYGC, PAX6 and CYP1B1. Eur J Hum Genet. 2014;22:907–15. [PMC free article: PMC4060118] [PubMed: 24281366]
• Qiao Y, Badduke C, Tang F, Cowieson D, Martell S, Lewis SME, Peñaherrera MS, Robinson WP, Volchuk A, Rajcan-Separovic E. Whole exome sequencing of families with 1q21.1 microdeletion or microduplication. Am J Med Genet A. 2017;173:1782-91. [PubMed: 28475290]
• Rabinowitz SS, Ahuja N, Gottfried J. Aripiprazole reversed gastroparesis in a child with 1q21.1-q21.2 microdeletion. BMJ Case Rep. 2018;2018:bcr2017223231. [PMC free article: PMC5878325] [PubMed: 29545430]
• Rees E, Walters JT, Georgieva L, Isles AR, Chambert KD, Richards AL, Mahoney-Davies G, Legge SE, Moran JL, McCarroll SA, O'Donovan MC, Owen MJ, Kirov G. Analysis of copy number variations at 15 schizophrenia-associated loci. Br J Psychiatry. 2014;204:108-14. [PMC free article: PMC3909838] [PubMed: 24311552]
• Rosenfeld JA, Coe BP, Eichler EE, Cuckle H, Shaffer LG. Estimates of penetrance for recurrent pathogenic copy-number variations. Genet Med. 2013;15:478-81. [PMC free article: PMC3664238] [PubMed: 23258348]
• Shaffer LG, Kashork CD, Saleki R, Rorem E, Sundin K, Ballif BC, Bejjani BA. Targeted genomic microarray analysis for identification of chromosome abnormalities in 1500 consecutive clinical cases. J Pediatr. 2006;149:98-102. [PubMed: 16860135]
• Soemedi R, Topf A, Wilson IJ, Darlay R, Rahman T, Glen E, Hall D, Huang N, Bentham J, Bhattacharya S, Cosgrove C, Brook JD, Granados-Riveron J, Setchfield K, Bu'lock F, Thornborough C, Devriendt K, Breckpot J, Hofbeck M, Lathrop M, Rauch A, Blue GM, Winlaw DS, Hurles M, Santibanez-Koref M, Cordell HJ, Goodship JA, Keavney BD. Phenotype-specific effect of chromosome 1q21.1 rearrangements and GJA5 duplications in 2436 congenital heart disease patients and 6760 controls. Hum Mol Genet. 2012;21:1513–20. [PMC free article: PMC3298277] [PubMed: 22199024]
• Stefansson H, Rujescu D, Cichon S, Pietiläinen OP, Ingason A, Steinberg S, Fossdal R, Sigurdsson E, Sigmundsson T, Buizer-Voskamp JE, Hansen T, Jakobsen KD, Muglia P, Francks C, Matthews PM, Gylfason A, Halldorsson BV, Gudbjartsson D, Thorgeirsson TE, Sigurdsson A, Jonasdottir A, Jonasdottir A, Bjornsson A, Mattiasdottir S, Blondal T, Haraldsson M, Magnusdottir BB, Giegling I, Möller HJ, Hartmann A, Shianna KV, Ge D, Need AC, Crombie C, Fraser G, Walker N, Lonnqvist J, Suvisaari J, Tuulio-Henriksson A, Paunio T, Toulopoulou T, Bramon E, Di Forti M, Murray R, Ruggeri M, Vassos E, Tosato S, Walshe M, Li T, Vasilescu C, Mühleisen TW, Wang AG, Ullum H, Djurovic S, Melle I, Olesen J, Kiemeney LA, Franke B. GROUP, Sabatti C, Freimer NB, Gulcher JR, Thorsteinsdottir U, Kong A, Andreassen OA, Ophoff RA, Georgi A, Rietschel M, Werge T, Petursson H, Goldstein DB, Nöthen MM, Peltonen L, Collier DA, St Clair D, Stefansson K. Large recurrent microdeletions associated with schizophrenia. Nature. 2008;455:232–6. [PMC free article: PMC2687075] [PubMed: 18668039]
• Velinov M, Dolzhanskaya N. Clavicular pseudoarthrosis, anomalous coronary artery and extra crease of the fifth finger-previously unreported features in individuals with class II 1q21.1 microdeletions. Eur J Med Genet. 2010;53:213–6. [PubMed: 20573555]
• Wagh VV, Vyas P, Agrawal S, Pachpor TA, Paralikar V, Khare SP. Peripheral blood-based gene expression studies in schizophrenia: a systematic review. Front Genet. 2021;12:736483. [PMC free article: PMC8548640] [PubMed: 34721526]
• Walsh T, McClellan JM, McCarthy SE, Addington AM, Pierce SB, Cooper GM, Nord AS, Kusenda M, Malhotra D, Bhandari A, Stray SM, Rippey CF, Roccanova P, Makarov V, Lakshmi B, Findling RL, Sikich L, Stromberg T, Merriman B, Gogtay N, Butler P, Eckstrand K, Noory L, Gochman P, Long R, Chen Z, Davis S, Baker C, Eichler EE, Meltzer PS, Nelson SF, Singleton AB, Lee MK, Rapoport JL, King MC, Sebat J. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science. 2008;320:539–43. [PubMed: 18369103]
• Wang J, Wang XC, Gu ZH, Ren GW, Zhao XH, Qu XK, Xu YJ, Yang YQ. A novel GJA5 variant associated with increased risk of essential hypertension. Am J Transl Res. 2023;15:1259-70. [PMC free article: PMC10006783] [PubMed: 36915790]
• Yoon J, Mao Y. Dissecting molecular genetic mechanisms of 1q21.1 CNV in neuropsychiatric disorders. Int J Mol Sci. 2021;22:5811. [PMC free article: PMC8197994] [PubMed: 34071723]
• Zaidi S, Choi M, Wakimoto H, Ma L, Jiang J, Overton JD, Romano-Adesman A, Bjornson RD, Breitbart RE, Brown KK, Carriero NJ, Cheung YH, Deanfield J, DePalma S, Fakhro KA, Glessner J, Hakonarson H, Italia MJ, Kaltman JR, Kaski J, Kim R, Kline JK, Lee T, Leipzig J, Lopez A, Mane SM, Mitchell LE, Newburger JW, Parfenov M, Pe'er I, Porter G, Roberts AE, Sachidanandam R, Sanders SJ, Seiden HS, State MW, Subramanian S, Tikhonova IR, Wang W, Warburton D, White PS, Williams IA, Zhao H, Seidman JG, Brueckner M, Chung WK, Gelb BD, Goldmuntz E, Seidman CE, Lifton RP. De novo mutations in histone-modifying genes in congenital heart disease. Nature. 2013;498:220–3. [PMC free article: PMC3706629] [PubMed: 23665959]