1q21.1 microdeletion syndrome
General Information (adopted from Orphanet):
Synonyms, Signs: |
Monosomy 1q21.1 Del(1)(q21) |
Number of Symptoms | 64 |
OrphanetNr: | 250989 |
OMIM Id: |
612474
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ICD-10: |
Q93.5 |
UMLs: |
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MeSH: |
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MedDRA: |
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Snomed: |
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Prevalence, inheritance and age of onset:
Prevalence: | No data available. |
Inheritance: |
Autosomal dominant Not applicable [Orphanet] |
Age of onset: |
Neonatal Infancy [Orphanet] |
Disease classification (adopted from Orphanet):
Parent Diseases: |
Partial deletion of the long arm of chromosome 1
-Rare developmental defect during embryogenesis -Rare genetic disease |
Symptom Information:
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(HPO:0000072) | Hydroureter | Occasional [Orphanet] | 146 / 7739 | |||
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(HPO:0000076) | Vesicoureteral reflux | Occasional [Orphanet] | 94 / 7739 | |||
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(HPO:0000035) | Abnormality of the testis | Occasional [Orphanet] | 296 / 7739 | |||
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(HPO:0002705) | High, narrow palate | Frequent [Orphanet] | 308 / 7739 | |||
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(HPO:0000414) | Bulbous nose | 63 / 7739 | ||||
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(HPO:0010296) | Ankyloglossia | Occasional [Orphanet] | 11 / 7739 | |||
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(HPO:0005105) | Abnormal nasal morphology | Frequent [Orphanet] | 114 / 7739 | |||
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(HPO:0000445) | Wide nose | Frequent [Orphanet] | 190 / 7739 | |||
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(HPO:0000286) | Epicanthus | Frequent [Orphanet] | 371 / 7739 | |||
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(HPO:0002007) | Frontal bossing | Frequent [Orphanet] | 366 / 7739 | |||
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(HPO:0000252) | Microcephaly | Frequent [Orphanet] | 832 / 7739 | |||
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(HPO:0000490) | Deeply set eye | Frequent [Orphanet] | 131 / 7739 | |||
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(HPO:0000343) | Long philtrum | Frequent [Orphanet] | 262 / 7739 | |||
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(HPO:0000518) | Cataract | Occasional [Orphanet] | 454 / 7739 | |||
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(HPO:0008056) | Aplasia/Hypoplasia affecting the eye | Occasional [Orphanet] | 142 / 7739 | |||
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(HPO:0000479) | Abnormality of the retina | Occasional [Orphanet] | 74 / 7739 | |||
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(HPO:0000612) | Iris coloboma | Occasional [Orphanet] | 116 / 7739 | |||
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(HPO:0000540) | Hypermetropia | Occasional [Orphanet] | 99 / 7739 | |||
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(HPO:0000486) | Strabismus | Occasional [Orphanet] | 576 / 7739 | |||
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(HPO:0000407) | Sensorineural hearing impairment | Occasional [Orphanet] | 524 / 7739 | |||
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(HPO:0002360) | Sleep disturbance | Occasional [Orphanet] | 113 / 7739 | |||
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(HPO:0000752) | Hyperactivity | Occasional [Orphanet] | 140 / 7739 | |||
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(HPO:0000708) | Behavioral abnormality | Occasional [Orphanet] | 212 / 7739 | |||
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(HPO:0001250) | Seizures | Occasional [Orphanet] | 1245 / 7739 | |||
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(HPO:0100851) | Abnormal emotion/affect behavior | Occasional [Orphanet] | 85 / 7739 | |||
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(HPO:0100753) | Schizophrenia | 20 / 7739 | ||||
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(HPO:0001249) | Intellectual disability | 1089 / 7739 | ||||
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(HPO:0000717) | Autism | Occasional [Orphanet] | 108 / 7739 | |||
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(HPO:0001172) | Abnormality of the thumb | Occasional [Orphanet] | 103 / 7739 | |||
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(HPO:0001829) | Foot polydactyly | Occasional [Orphanet] | 41 / 7739 | |||
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(HPO:0004279) | Short palm | Occasional [Orphanet] | 323 / 7739 | |||
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(HPO:0001382) | Joint hypermobility | Occasional [Orphanet] | 231 / 7739 | |||
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(HPO:0011304) | Broad thumb | 39 / 7739 | ||||
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(HPO:0001770) | Toe syndactyly | Occasional [Orphanet] | 149 / 7739 | |||
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(HPO:0004209) | Clinodactyly of the 5th finger | Occasional [Orphanet] | 288 / 7739 | |||
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(HPO:0001762) | Talipes equinovarus | Occasional [Orphanet] | 309 / 7739 | |||
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(HPO:0010055) | Broad hallux | Occasional [Orphanet] | 56 / 7739 | |||
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(HPO:0002650) | Scoliosis | Occasional [Orphanet] | 705 / 7739 | |||
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(HPO:0001161) | Hand polydactyly | Occasional [Orphanet] | 71 / 7739 | |||
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(HPO:0001773) | Short foot | Occasional [Orphanet] | 86 / 7739 | |||
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(HPO:0004299) | Hernia of the abdominal wall | Occasional [Orphanet] | 176 / 7739 | |||
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(HPO:0004325) | Decreased body weight | Occasional [Orphanet] | 492 / 7739 | |||
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(HPO:0001511) | Intrauterine growth retardation | Occasional [Orphanet] | 358 / 7739 | |||
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(HPO:0004322) | Short stature | Frequent [Orphanet] | 1232 / 7739 | |||
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(HPO:0001680) | Coarctation of aorta | 57 / 7739 | ||||
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(HPO:0001660) | Truncus arteriosus | 21 / 7739 | ||||
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(HPO:0012303) | Abnormality of the aortic arch | Occasional [Orphanet] | 57 / 7739 | |||
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(HPO:0001643) | Patent ductus arteriosus | Occasional [Orphanet] | 228 / 7739 | |||
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(HPO:0001669) | Transposition of the great arteries | 36 / 7739 | ||||
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(HPO:0004760) | Congenital septal defect | Occasional [Orphanet] | 69 / 7739 | |||
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(HPO:0003220) | Abnormality of chromosome stability | Very frequent [Orphanet] | 98 / 7739 | |||
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(HPO:0001252) | Muscular hypotonia | Occasional [Orphanet] | 990 / 7739 | |||
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(OMIM) | Normal neurological development is possible | 1 / 7739 | ||||
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(OMIM) | Normal or reduced | 1 / 7739 | ||||
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(HPO:0003829) | Incomplete penetrance | 85 / 7739 | ||||
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(OMIM) | Broad halluces | 12 / 7739 | ||||
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(OMIM) | Bicuspid aortic valve with aneurysm | 1 / 7739 | ||||
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(HPO:0000006) | Autosomal dominant inheritance | 2518 / 7739 | ||||
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(HPO:0012758) | Neurodevelopmental delay | Frequent [Orphanet] | 949 / 7739 | |||
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(HPO:0000238) | Hydrocephalus | Occasional [Orphanet] | 278 / 7739 | |||
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(HPO:0007370) | Aplasia/Hypoplasia of the corpus callosum | Occasional [Orphanet] | 180 / 7739 | |||
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(OMIM) | Mental retardation, mild to moderate | 33 / 7739 | ||||
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(OMIM) | Duplicated or bifid halluces (minority) | 1 / 7739 | ||||
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(OMIM) | Mild dysmorphism | 2 / 7739 |
Associated genes:
ClinVar (via SNiPA)
Gene symbol | Variation | Clinical significance | Reference |
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Additional Information:
Clinical Description OMIM |
Among 21 patients with a 1.35-Mb deletion in chromosome 1q21.1, Mefford et al. (2008) found considerable variability in the level of phenotypic expression of the microdeletion; phenotypes included mild to moderate mental retardation, microcephaly, cardiac abnormalities, and cataracts. ... |
Molecular genetics OMIM |
By screening 5,218 patients with unexplained mental retardation, autism, or congenital anomalies for the presence of microdeletions or microduplications in chromosome 1q21.1, Mefford et al. (2008) identified 25 individuals with a recurrent 1.35-Mb deletion. Of the 21 probands ... |
Diagnosis GeneReviews | 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:... Chromosomal RegionTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test Availability1q21.1 | Deletion / duplication analysis 2Recurrent 1.35-Mb deletion 100%Clinical1. The ability of the test method used to detect a deletion or duplication that is present in the indicated chromosomal region2. 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. 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. 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]
Clinical Description GeneReviews | 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. ... FrequencyFeatures>75% | Variable/mild dysmorphic facial features
Differential Diagnosis GeneReviews | The 22q11.2 microdeletion syndrome is the most common microdeletion syndrome and has several features that overlap with those seen in individuals with the recurrent distal 1.35-Mb 1q21.1 deletion: developmental delays, learning disabilities (though not in 1q21.1 microdeletions the predominant nonverbal learning disability seen in 22q11.2 microdeletions), intellectual disability, behavioral abnormalities, short stature, eye abnormalities, cardiac defects, and schizophrenia. However, persons with a distal 1.35-Mb 1q21.1 deletion do not have the typical facial characteristics seen in the 22q11.2 microdeletion syndrome. Brunet et al [2009] identified two individuals with 1q21.1 copy number abnormalities who had clinical findings suggestive of a 22q11.2 microdeletion. One individual (who was previously reported in Mefford et al [2008]) had a duplication of the region that is typically deleted in individuals with thrombocytopenia absent radius (TAR) syndrome and a microdeletion of distal 1.35-Mb 1q21.1 on the same chromosome; the other had a duplication of the TAR-associated region only.... |
Management GeneReviews | 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:... |
Molecular genetics GeneReviews |
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.... Gene SymbolChromosomal LocusProtein NameNot applicable1q21 | Not applicableData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for 1q21.1 Microdeletion (View All in OMIM) View in own window 612474CHROMOSOME 1q21.1 DELETION SYNDROME, 1.35-MBMolecular 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), 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].