22q13 deletion syndrome
22q13 deletion syndrome | |
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Other names | Phelan–McDermid syndrome |
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Chromosome 22 mutations cause 22q13 syndrome. | |
Specialty | Genetics ![]() |
22q13 deletion syndrome, also known as Phelan–McDermid syndrome (PMS), is a genetic disorder caused by deletions or rearrangements on the q terminal end (long arm) of chromosome 22. Any abnormal genetic variation in the q13 region that presents with significant manifestations (phenotype) typical of a terminal deletion may be diagnosed as 22q13 deletion syndrome. There is disagreement among researchers as to the exact definition of 22q13 deletion syndrome.[1] The Developmental Synaptopathies Consortium defines PMS as being caused by SHANK3 mutations, a definition that appears to exclude terminal deletions.[2] The requirement to include SHANK3 in the definition is supported by many but not by those who first described 22q13 deletion syndrome.[3]
Prototypical terminal deletion of 22q13 can be uncovered by karyotype analysis, but many terminal and interstitial deletions are too small. The availability of DNA microarray technology for revealing multiple genetic problems simultaneously has been the diagnostic tool of choice. The falling cost for the whole exome sequencing and, eventually, whole genome sequencing, may replace DNA microarray technology for candidate evaluation. However, fluorescence in situ hybridization (FISH) tests remain valuable for diagnosing cases of mosaicism (mosaic genetics) and chromosomal rearrangements (e.g., ring chromosome, unbalanced chromosomal translocation). Although early researchers sought a monogenic (single gene genetic disorder) explanation, recent studies have not supported that hypothesis (see Etiology).
Signs and symptoms
Affected individuals present with a broad array of medical and behavioral manifestations (tables 1 and 2).[4][5][6][7] Patients are consistently characterized by global developmental delay, intellectual disability, speech abnormalities, ASD-like behaviors, hypotonia and mild dysmorphic features.[4][6][7][8][9][10][11][12][13][14][15][16] Table 1 summarizes the dysmorphic and medical conditions that have been reported in individuals with PMS. Table 2 summarizes the psychiatric and neurological symptoms associated with PMS. Most of the studies include small samples or relied on parental report or medical record review to collect information, which can account in part for the variability in the presentation of some of the presenting features. Larger prospective studies are needed to further characterize the phenotype.
Dysmorphic feature | Percentage (%) | Medical comorbidities | Percentage (%) |
---|---|---|---|
Macrocephaly | 7–31 | Hypothyroidism | 3–6 |
Microcephaly | 11–14 | Sleep disturbance | 41–46 |
Dolichocephaly | 23–86 | Gastroesophageal reflux | 42–44 |
Long eyelashes | 43–93 | Increased pain threshold | 10–88 |
Bulbous nose | 47–80 | Constipation/diarrhea | 38–41 |
High-arched palate | 25–47 | Brain imaging abnormalities | 7–75 |
Malocclusion/widely spaced teeth | 19 | Recurrent upper respiratory infections | 8–53 |
Full cheeks | 25 | Renal abnormalities | 17–26 |
Pointed chin | 22–62 | Lymphedema | 8–53 |
Large fleshy hands | 33–68 | Seizures | 14–41 |
Hypoplastic/dysplastic nails | 3–78 | Strabismus | 6–26 |
Hyper-extensibility | 25–61 | Short stature | 11–13 |
Abnormal spine curvature | 22 | Tall stature/accelerated growth | 3–18 |
Sacral dimple | 13–37 | Cardiac defects | 3–25 |
Syndactyly of toes 2 and 3 | 48 | Precocious or delayed puberty | 12 |
Psychiatric and neurologic manifestations | Percentage (%) |
---|---|
Autism spectrum disorder | >25 |
Intellectual disability | ~100 |
Global developmental delay | ~100 |
Absent or severely affected speech | >75 |
Sensory seeking behaviors (mouthing of objects) | >25 |
Teeth grinding | >25 |
Hyperactivity and inattention | >50 |
Stereotypical movements | >50 |
Hypotonia | >50 |
Fine and gross motor abnormalities | >90 |
Poor fine motor coordination | >90 |
Gait abnormalities | >90 |
Visual tracking abnormalities | >85 |
Seizure disorder | 17–41 |
Brain structural abnormalities | 44–100 |
Sleep problems | >40 |
Cause
Various deletions affect the terminal region of the long arm of chromosome 22 (the paternal chromosome in 75% of cases,[citation needed]) from 22q13.3 to 22qter. Although the deletion is most typically a result of a de novo mutation, there is an inherited form resulting from familial chromosomal translocations involving the 22 chromosome. In the de novo form, the size of the terminal deletion is variable and can go from 130 Kb (130,000 base pairs) to 9 Mb. Deletions smaller than 1 Mb are very rare (about 3%). The remaining 97% of terminal deletions impact about 30 to 190 genes (see list, below). At one time it was thought that deletion size was not related to the core clinical features.[17] That observation lead to an emphasis on the SHANK3 gene, which resides close to the terminal end of chromosome 22. Interest in SHANK3 grew as it became associated with autism spectrum disorder (ASD) and Schizophrenia.[18] Since then, twelve other genes on 22q13 (MAPK8IP2,[19] CHKB,[20] SCO2,[21] SBF1,[22] PLXNB2,[23] MAPK12,[24] PANX2,[25] BRD1,[26] CELSR1,[27] WNT7B,[28] TCF20[29]) have been associated with autism spectrum disorder and/or Schizophrenia (see references below). Some mutations of SHANK3 mimic 22q13 deletion syndrome, but SHANK3 mutations and microdeletions have quite variable impact.[citation needed]
Some of the core features of 22q13 deletion syndrome are dependent upon deletion size, and do not depend on the loss of SHANK3.[30][31][32] As noted above, the distal 1 Mb of 22q is a gene rich region. There are too few clinical cases to statistically measure the relationship between deletion size and phenotype in this region. SHANK3 is also adjacent to a gene cluster (ARSA and MAPK8IP2)[33] that has a high probability of contributing to ASD,[34] suggesting the effects of SHANK3 deletion may be indistinguishable from other genetic losses. A landmark study of induced pluripotent stem cell neurons cultured from patients with 22q13 deletion syndrome shows that restoration of the SHANK3 protein produces a significant, but incomplete rescue of membrane receptors, supporting both a substantial role for SHANK3 and an additional role for other genes in the distal 1 Mb of chromosome 22.[35]
There is an interest in the impact of MAPK8IP2 (also called IB2) in 22q13 deletion syndrome.[36] MAPK8IP2 is especially interesting because it regulates the balance between NMDA receptors and AMPA receptors.[37] The genes SULT4A1[38] and PARVB[39] may cause 22q13 deletion syndrome in cases of more proximal interstitial and large terminal deletions.[32] There are about 187 protein coding genes in the 22q13 region.[40] A group of genes (MPPED1,[41] CYB5R3,[42] FBLN1,[43] NUP50,[44] C22ORF9,[45] KIAA1644,[46] PARVB,[39] TRMU,[47] WNT7B[48] and ATXN10[49]), as well as microRNAs may all contribute to loss of language, a feature that varies notably with deletion size.[50] The same study found that macrocephaly seen in 22q13 deletion syndrome patients may be associated with WNT7B. FBLN1 is responsible for synpolydactyly as well as its contribution to the neurological manifestations (OMIM 608180).
RABL2B | ACR | SHANK3 | ARSA | MAPK8IP2 | CHKB | CPT1B | SYCE3 | KLHDC7B | ODF3B | TYMP | SCO2 |
NCAPH2 | LMF2 | MIOX | ADM2 | SBF1 | PPP6R2 | DENND6B | PLXNB2 | MAPK11 | MAPK12 | HDAC10 | TUBGCP6 |
SELO | TRABD | PANX2 | MOV10L1 | MLC1 | IL17REL | PIM3 | CRELD2 | ALG12 | ZBED4 | BRD1 | FAM19A5 |
FLJ32756 | TBC1D22A | CERK | GRAMD4 | CELSR1 | TRMU | BC069212 | GTSE1 | TTC38 | PKDREJ | CDPF1 | PPARA |
WNT7B | ATXN10 | FBLN1 | RIBC2 | SMC1B | FAM118A | UPK3A | KIAA0930 | NUP50 | PHF21B | PRR5-ARHGAP8 | LDOC1L |
KIAA1644 | PARVG | TRNA_SeC | PARVB | SAMM50 | PNPLA3 | PNPLA5 | SULT4A1 | EFCAB6 | MPPED1 | SCUBE1 | TTLL12 |
TSPO | MCAT | BIK | TTLL1 | PACSIN2 | ARFGAP3 | A4GALT | ATP5L2 | DL490307 | CYB5R3 | RNU12 | POLDIP3 |
SERHL2 | RRP7A | NFAM1 | TCF20 | CYP2D6 | NDUFA6 | SMDT1 | FAM109B | NAGA | WBP2NL | CENPM | TNFRSF13C |
SHISA8 | SREBF2 | CCDC134 | MEI1 | C22orf46 | NHP2L1 | XRCC6 | DESI1 | PMM1 | CSDC2 | POLR3H | ACO2 |
PHF5A | TOB2 | TEF | ZC3H7B | RANGAP1 | CHADL | L3MBTL2 | EP300 | RBX1 | DNAJB7 | XPNPEP3 | ST13 |
SLC25A17 | MCHR1 | MKL1 | SGSM3 | ADSL | TNRC6B | FAM83F | GRAP2 | ENTHD1 | CACNA1I | RPS19BP1 | ATF4 |
SMCR7L | MGAT3 | TAB1 | SNORD43 | RPL3 | PDGFB | CBX7 | APOBEC3H | APOBEC3F | APOBEC3D | APOBEC3C | APOBEC3B |
CBX6 | NPTXR | DNAL4 | SUN2 | GTPBP1 | JOSD1 | TOMM22 | CBY1 | FAM227A | DMC1 | DDX17 | KDELR3 |
KCNJ4 | CSNK1E | TMEM184B | MAFF | MAFF | PLA2G6 | BAIAP2L2 | SLC16A8 | PICK1 | SOX10 | POLR2F | C22orf23 |
MICALL1 | EIF3L | ANKRD54 | GALR3 | GCAT | H1F0 | TRIOBP | NOL12 | LGALS1 | SH3BP1 | GGA1 | LGALS2 |
CDC42EP1 | CARD10 | MFNG | ELFN2 | CYTH4 |
Table of protein coding genes involved in 22q13 deletion syndrome (based on Human Genome Browser – hg38 assembly [51]). Underline identifies 13 genes that are associated with autism.[52][53][54][55] Bold identifies genes associated with hypotonia (based on Human Phenotype Browser [56] search for 'hypotonia' and the OMIM database [57]).
Diagnosis and management
Clinical genetics and genetic testing
Genetic testing is necessary to confirm the diagnosis of PMS. A prototypical terminal deletion of 22q13 can be uncovered by karyotype analysis, but many terminal and interstitial deletions are too small to detect with this method.[8][58] Chromosomal microarray should be ordered in children with suspected developmental delays or ASD.[59][60] Most cases will be identified by microarray; however, small variations in genes might be missed. The falling cost for whole exome sequencing may replace DNA microarray technology for candidate gene evaluation. Biological parents should be tested with fluorescence in situ hybridization (FISH) to rule out balanced translocations or inversions. Balanced translocation in a parent increases the risk for recurrence and heritability within families (figure 3).[61]
Clinical genetic evaluations and dysmorphology exams should be done to evaluate growth, pubertal development, dysmorphic features (table 1) and screen for organ defects (table 2)
Cognitive and behavioral assessment
All patients should undergo comprehensive developmental, cognitive and behavioral assessments by clinicians with experience in developmental disorders. Cognitive evaluation should be tailored for individuals with significant language and developmental delays.[8] All patients should be referred for specialized speech/language, occupational and physical therapy evaluations.
Neurological management
Individuals with PMS should be followed by a pediatric neurologist regularly to monitor motor development, coordination, and gait, as well as conditions that might be associated with hypotonia.[9] Head circumference should be performed routinely up until 36 months. Given the high rate of seizure disorders (up to 41% of patients) reported in the literature in patients with PMS and its overall negative impact on development, an overnight video EEG should be considered early to rule out seizure activity. In addition, a baseline structural brain MRI should be considered to rule out the presence of structural abnormalities.[5]
Nephrology
All patients should have a baseline renal and bladder ultrasonography and a voiding cystourethrogram should be considered to rule out structural and functional abnormalities. Renal abnormalities are reported in up to 38% of patients with PMS.[62][63] Vesicouretral reflux, hydronephrosis, renal agenesis, dysplastic kidney, polycystic kidney and recurrent urinary tract infections have all been reported in patients with PMS.
Cardiology
Congenital heart defects (CHD) are reported in samples of children with PMS with varying frequency (up to 25%)(29,36). The most common CHD include tricuspid valve regurgitation, atrial septal defects and patent ductus arteriosus. Cardiac evaluation, including echocardiography and electrocardiogram, should be considered.[8]
Gastroenterology
Gastrointestinal symptoms are common in individuals with PMS. Gastroesophageal reflux, constipation, diarrhea and cyclic vomiting are frequently described.[64]
Table 3: Clinical Assessment Recommendations in Phelan McDermid Syndrome
Medical Specialty | Assessment Recommended |
Primary Care/Development Pediatrics | Careful and routine monitoring |
Hearing Assessment | |
Visual Assessment | |
Monitoring of height, weight, and BMI | |
Otolaryngology (ENT) | |
Pediatric dentistry | |
Physiatrist/physical therapy | |
Psychiatric and Psychology | Psychiatric evaluation with a focus on autism spectrum disorder |
Autism Diagnostic Observation Schedule (ADOS) | |
Cognitive or Developmental Assessment | |
Speech and Language Evaluation/Therapy | |
Adaptive Function Testing | |
Educational Assessment | |
Occupational Therapy | |
Neurology | motor development, coordination, and gait monitoring, as well as conditions that might be associated with hypotonia, like neuromuscular scoliosis and feeding problems |
Overnight video EEG | |
Structural brain MRI | |
Head circumference up to 36 months | |
Nephrology | Renal and bladder ultrasonography |
Cardiology | Echocardiogram |
Electrocardiogram | |
Endocrinology | Thyroid function |
Nutritional assessment |
Epidemiology
The true prevalence of PMS has not been determined. More than 1,200 people have been identified worldwide according to the Phelan–McDermid Syndrome Foundation.[citation needed] However, it is believed to be underdiagnosed due to inadequate genetic testing and lack of specific clinical features. It is known to occur with equal frequency in males and females. Studies using chromosomal microarray for diagnosis indicate that at least 0.5% of cases of ASD can be explained by mutations or deletions in the SHANK3 gene.[58] In addition, when ASD is associated with ID, SHANK3 mutations or deletions have been found in up to 2% of individuals.[65][66]
History
The first case of PMS was described in 1985 by Watt et al., who described a 14-year-old boy with severe intellectual disability, mild dysmorphic features and absent speech, which was associated with terminal loss of the distal arm of chromosome 22.[67] In 1988, Phelan et al. described a similar clinical presentation associated with a de novo deletion in 22q13.3. Subsequent cases were described in the following years with a similar clinical presentation. Phelan et al. (2001), compared 37 subjects with 22q13 deletions with features of 24 cases described in the literature finding that the most common features were global developmental delay, absent or delayed speech and hypotonia. In 2001, Bonaglia et al.,[68] described a case that associated the 22q.13 deletion syndrome with a disruption of the SHANK3 gene (also called ProSAP2). The following year, Anderlid et al. (2002),[69] refined the area in 22q13 presumably responsible for the common phenotypic presentation of the syndrome to a 100kb in 22q13.3. Out of the three genes affected, SHANK3 was identified as the critical gene due to its expression pattern and function. Wilson et al.[70] (2003) evaluated 56 patients with the clinical presentation of PMS, all of whom had a functional loss of one copy of the SHANK3 gene. However, later the same group demonstrated that loss of SHANK3 gene was not an essential requirement for the disorder.[71]
See also
Notes
- ^ Phelan K, Boccuto L, Rogers RC, Sarasua SM, McDermid HE (2015). "Letter to the editor regarding Disciglio et al.: interstitial 22q13 deletions not involving SHANK3 gene: a new contiguous gene syndrome". Am J Med Genet A. 167 (7): 1679–80. doi:10.1002/ajmg.a.36788. PMID 26295085. S2CID 36651351.
- ^ https://www.rarediseasesnetwork.org/cms/dsc/About-Us (downloaded 21-September-2015)
- ^ Phelan MC, McDermid HE (2011). "The 22q13.3 Deletion Syndrome (Phelan-McDermid Syndrome)". Mol Syndromol. 2 (1): 186–201. doi:10.1159/000334260. PMC 3366702. PMID 22670140.
- ^ a b Sarasua, Sara M.; Dwivedi, Alka; Boccuto, Luigi; Chen, Chin-Fu; Sharp, Julia L.; Rollins, Jonathan D.; Collins, Julianne S.; Rogers, R. Curtis; Phelan, Katy (2014-04-01). "22q13.2q13.32 genomic regions associated with severity of speech delay, developmental delay, and physical features in Phelan-McDermid syndrome". Genetics in Medicine. 16 (4): 318–328. doi:10.1038/gim.2013.144. ISSN 1530-0366. PMID 24136618.
- ^ a b Philippe, Anne; Boddaert, Nathalie; Vaivre-Douret, Laurence; Robel, Laurence; Danon-Boileau, Laurent; Malan, Valérie; Blois, Marie-Christine de; Heron, Delphine; Colleaux, Laurence (2008-08-01). "Neurobehavioral Profile and Brain Imaging Study of the 22q13.3 Deletion Syndrome in Childhood". Pediatrics. 122 (2): e376–e382. doi:10.1542/peds.2007-2584. ISSN 0031-4005. PMID 18625665. S2CID 3276179.
- ^ a b Sarasua, Sara M.; Dwivedi, Alka; Boccuto, Luigi; Rollins, Jonathan D.; Chen, Chin-Fu; Rogers, R. Curtis; Phelan, Katy; DuPont, Barbara R.; Collins, Julianne S. (2011-11-01). "Association between deletion size and important phenotypes expands the genomic region of interest in Phelan-McDermid syndrome (22q13 deletion syndrome)". Journal of Medical Genetics. 48 (11): 761–766. doi:10.1136/jmedgenet-2011-100225. ISSN 1468-6244. PMID 21984749. S2CID 28620399.
- ^ a b Luciani, J. J.; de Mas, P.; Depetris, D.; Mignon-Ravix, C.; Bottani, A.; Prieur, M.; Jonveaux, P.; Philippe, A.; Bourrouillou, G. (2003-09-01). "Telomeric 22q13 deletions resulting from rings, simple deletions, and translocations: cytogenetic, molecular, and clinical analyses of 32 new observations". Journal of Medical Genetics. 40 (9): 690–696. doi:10.1136/jmg.40.9.690. ISSN 1468-6244. PMC 1735584. PMID 12960216.
- ^ a b c d Kolevzon, Alexander; Angarita, Benjamin; Bush, Lauren; Wang, A. Ting; Frank, Yitzchak; Yang, Amy; Rapaport, Robert; Saland, Jeffrey; Srivastava, Shubhika (2014-01-01). "Phelan-McDermid syndrome: a review of the literature and practice parameters for medical assessment and monitoring". Journal of Neurodevelopmental Disorders. 6 (1): 39. doi:10.1186/1866-1955-6-39. ISSN 1866-1947. PMC 4362650. PMID 25784960.
- ^ a b Manning, Melanie A.; Cassidy, Suzanne B.; Clericuzio, Carol; Cherry, Athena M.; Schwartz, Stuart; Hudgins, Louanne; Enns, Gregory M.; Hoyme, H. Eugene (2004-08-01). "Terminal 22q deletion syndrome: a newly recognized cause of speech and language disability in the autism spectrum". Pediatrics. 114 (2): 451–457. doi:10.1542/peds.114.2.451. ISSN 1098-4275. PMID 15286229.
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- ^ Koolen, David A.; Reardon, William; Rosser, Elisabeth M.; Lacombe, Didier; Hurst, Jane A.; Law, Caroline J.; Bongers, Ernie M. H. F.; van Ravenswaaij-Arts, Conny M.; Leisink, Martijn A. R. (2005-09-01). "Molecular characterisation of patients with subtelomeric 22q abnormalities using chromosome specific array-based comparative genomic hybridisation". European Journal of Human Genetics. 13 (9): 1019–1024. doi:10.1038/sj.ejhg.5201456. ISSN 1018-4813. PMID 15986041.
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- ^ Rollins, Jonathan D.; Sarasua, Sara M.; Phelan, Katy; DuPont, Barbara R.; Rogers, R. Curtis; Collins, Julianne S. (2011-09-01). "Growth in Phelan-McDermid syndrome". American Journal of Medical Genetics Part A. 155A (9): 2324–2326. doi:10.1002/ajmg.a.34158. ISSN 1552-4833. PMID 21834045. S2CID 20565974.
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- ^ Wilson HL, Wong AC, Shaw SR, et al. (2003). "Molecular characterisation of the 22q13 deletion syndrome supports the role of haploinsufficiency of SHANK3/PROSAP2 in the major neurological symptoms". J. Med. Genet. 40 (8): 575–84. doi:10.1136/jmg.40.8.575. PMC 1735560. PMID 12920066.
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- ^ "MAPK8IP2 Gene - GeneCards | JIP2 Protein | JIP2 Antibody".
- ^ "CHKB Gene - GeneCards | CHKB Protein | CHKB Antibody".
- ^ "SCO2 Gene - GeneCards | SCO2 Protein | SCO2 Antibody". www.genecards.org.
- ^ "SBF1 Gene - GeneCards | MTMR5 Protein | MTMR5 Antibody".
- ^ "PLXNB2 Gene - GeneCards | PLXB2 Protein | PLXB2 Antibody".
- ^ "MAPK12 Gene - GeneCards | MK12 Protein | MK12 Antibody".
- ^ "Panx2 related genes - GeneCards Search Results".
- ^ "Brd1 related genes - GeneCards Search Results".
- ^ "CELSR1 Gene - GeneCards | CELR1 Protein | CELR1 Antibody".
- ^ "WNT7B Gene - GeneCards | WNT7B Protein | WNT7B Antibody".
- ^ "TCF20 Gene - GeneCards | TCF20 Protein | TCF20 Antibody".
- ^ Sarasua, SM; et al. (2011). "Association between deletion size and important phenotypes expands the genomic region of interest in Phelan-McDermid syndrome (22q13 deletion syndrome)". J Med Genet. 48 (11): 761–6. doi:10.1136/jmedgenet-2011-100225. PMID 21984749. S2CID 28620399.
- ^ Simenson, K; et al. (2013). "A patient with the classic features of Phelan-McDermid syndrome and a high immunoglobulin E level caused by a cryptic interstitial 0.72-Mb deletion in the 22q13.2 region". Am J Med Genet A. 164A (3): 806–9. doi:10.1002/ajmg.a.36358. PMID 24375995. S2CID 7917552.
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- ^ "SULT4A1 Gene - GeneCards | ST4A1 Protein | ST4A1 Antibody".
- ^ a b "PARVB Gene - GeneCards | PARVB Protein | PARVB Antibody".
- ^ "UCSC Genome Browser Home". genome.ucsc.edu.
- ^ "MPPED1 Gene - GeneCards | MPPD1 Protein | MPPD1 Antibody".
- ^ "CYB5R3 Gene - GeneCards | NB5R3 Protein | NB5R3 Antibody".
- ^ "FBLN1 Gene - GeneCards | FBLN1 Protein | FBLN1 Antibody".
- ^ "NUP50 Gene - GeneCards | NUP50 Protein | NUP50 Antibody".
- ^ "KIAA0930 Gene - GeneCards | K0930 Protein | K0930 Antibody".
- ^ "SHISAL1 Gene - GeneCards | SHSL1 Protein | SHSL1 Antibody".
- ^ "TRMU Gene - GeneCards | MTU1 Protein | MTU1 Antibody".
- ^ "WNT7B Gene - GeneCards | WNT7B Protein | WNT7B Antibody".
- ^ "ATXN10 Gene - GeneCards | ATX10 Protein | ATX10 Antibody".
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- ^ Home | Human Phenotype Ontology
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References
- Bonaglia MC, Giorda R, Mani E, et al. (2006). "Identification of a recurrent breakpoint within the SHANK3 gene in the 22q13.3 deletion syndrome". J. Med. Genet. 43 (10): 822–8. doi:10.1136/jmg.2005.038604. PMC 2563164. PMID 16284256.
- Manning MA, Cassidy SB, Clericuzio C, et al. (2004). "Terminal 22q deletion syndrome: a newly recognized cause of speech and language disability in the autism spectrum". Pediatrics. 114 (2): 451–7. doi:10.1542/peds.114.2.451. PMID 15286229.
- Phelan MC, Rogers RC, Saul RA, et al. (2001). "22q13 deletion syndrome". Am. J. Med. Genet. 101 (2): 91–9. doi:10.1002/1096-8628(20010615)101:2<91::AID-AJMG1340>3.0.CO;2-C. PMID 11391650.
- 22q13.org "22q13 deletion syndrome home"
- Phelan MC, McDermid HE (2011). "The 22q13.3 Deletion Syndrome (Phelan-McDermid Syndrome)". Mol Syndromol. 2 (1): 186–201. doi:10.1159/000334260. PMC 3366702. PMID 22670140.
External links
- DECIPHER database entry for 22q13 deletion syndrome