22q13 deletion syndrome

Signs and symptoms

Affected individuals present with a broad array of medical and behavioral manifestations (tables 1 and 2). Patients are consistently characterized by global developmental delay, intellectual disability, speech abnormalities, ASD-like behaviors, hypotonia and mild dysmorphic features. 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.

Cause

Various deletions affect the terminal region of the long arm of chromosome 22 (the paternal chromosome in 75% of cases,) 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. 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. Since then, twelve other genes on 22q13 (MAPK8IP2, CHKB, SCO2, SBF1, PLXNB2, MAPK12, PANX2, BRD1, CELSR1, WNT7B, TCF20) 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.

Some of the core features of 22q13 deletion syndrome are dependent upon deletion size, and do not depend on the loss of SHANK3. 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) that has a high probability of contributing to ASD, 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.

There is an interest in the impact of MAPK8IP2 (also called IB2) in 22q13 deletion syndrome. MAPK8IP2 is especially interesting because it regulates the balance between NMDA receptors and AMPA receptors. The genes SULT4A1 and PARVB may cause 22q13 deletion syndrome in cases of more proximal interstitial and large terminal deletions. A group of genes (MPPED1, CYB5R3, FBLN1, NUP50, C22ORF9, KIAA1644, PARVB, TRMU, WNT7B and ATXN10), as well as microRNAs may all contribute to loss of language, a feature that varies notably with deletion size. 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).

Table of protein coding genes involved in 22q13 deletion syndrome (based on Human Genome Browser – hg38 assembly). Underline identifies 13 genes that are associated with autism. Bold identifies genes associated with hypotonia (based on Human Phenotype Browser search for 'hypotonia' and the OMIM database).

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. 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).

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. 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. 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.

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. 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.

Gastroenterology

Gastrointestinal symptoms are common in individuals with PMS. Gastroesophageal reflux, constipation, diarrhea and cyclic vomiting are frequently described.

Table 3: Clinical Assessment Recommendations in Phelan–McDermid Syndrome

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. 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. In addition, when ASD is associated with ID, SHANK3 mutations or deletions have been found in up to 2% of individuals.

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. 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., 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), 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. (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.

Notes

References

• 22q13.org "22q13 deletion syndrome home"

References

1. (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.
2. https://www.rarediseasesnetwork.org/cms/dsc/About-Us (downloaded 21-September-2015)
3. (2011). "The 22q13.3 Deletion Syndrome (Phelan-McDermid Syndrome).". Mol Syndromol.
4. (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.
5. (2008-08-01). "Neurobehavioral Profile and Brain Imaging Study of the 22q13.3 Deletion Syndrome in Childhood". Pediatrics.
6. (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.
7. (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.
8. (2014-01-01). "Phelan-McDermid syndrome: a review of the literature and practice parameters for medical assessment and monitoring". Journal of Neurodevelopmental Disorders.
9. (2004-08-01). "Terminal 22q deletion syndrome: a newly recognized cause of speech and language disability in the autism spectrum". Pediatrics.
10. (1994-03-01). "Clinical, cytogenetic, and molecular characterization of seven patients with deletions of chromosome 22q13.3.". American Journal of Human Genetics.
11. (2005-09-01). "Molecular characterisation of patients with subtelomeric 22q abnormalities using chromosome specific array-based comparative genomic hybridisation". European Journal of Human Genetics.
12. (2013-01-01). "Molecular and phenotypic characterization of ring chromosome 22 in two unrelated patients". Cytogenetic and Genome Research.
13. (2007-11-15). "22q13.3 deletion syndrome: a recognizable malformation syndrome associated with marked speech and language delay". American Journal of Medical Genetics Part C.
14. (2011-09-01). "Growth in Phelan-McDermid syndrome". American Journal of Medical Genetics Part A.
15. (2010-03-01). "22q13.3 Deletion Syndrome: Clinical and Molecular Analysis Using Array CGH". American Journal of Medical Genetics Part A.
16. (2012). "Neuropsychopathology in 7 Patients with the 22q13 Deletion Syndrome: Presence of Bipolar Disorder and Progressive Loss of Skills". Molecular Syndromology.
17. (2003). "Molecular characterisation of the 22q13 deletion syndrome supports the role of haploinsufficiency of ''SHANK3''/''PROSAP2'' in the major neurological symptoms". J. Med. Genet..
18. (2010). "De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia". Proc. Natl. Acad. Sci. USA.
19. "MAPK8IP2 Gene - GeneCards | JIP2 Protein | JIP2 Antibody".
20. "CHKB Gene - GeneCards | CHKB Protein | CHKB Antibody".
21. "SCO2 Gene - GeneCards | SCO2 Protein | SCO2 Antibody".
22. "SBF1 Gene - GeneCards | MTMR5 Protein | MTMR5 Antibody".
23. "PLXNB2 Gene - GeneCards | PLXB2 Protein | PLXB2 Antibody".
24. "MAPK12 Gene - GeneCards | MK12 Protein | MK12 Antibody".
25. "Panx2 related genes - GeneCards Search Results".
26. "Brd1 related genes - GeneCards Search Results".
27. "CELSR1 Gene - GeneCards | CELR1 Protein | CELR1 Antibody".
28. "WNT7B Gene - GeneCards | WNT7B Protein | WNT7B Antibody".
29. "TCF20 Gene - GeneCards | TCF20 Protein | TCF20 Antibody".
30. (2011). "Association between deletion size and important phenotypes expands the genomic region of interest in Phelan-McDermid syndrome (22q13 deletion syndrome).". J Med Genet.
31. (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.
32. (2014). "Interstitial 22q13 Deletions Not Involving SHANK3 Gene: A New Contiguous Gene Syndrome.". Am J Med Genet A.
33. (2015). "The clustering of functionally related genes contributes to CNV-mediated disease.". [[Genome Res]].
34. (2016). "Genome-wide prediction and functional characterization of the genetic basis of autism spectrum disorder.". [[Nature Neuroscience]].
35. (2013). "SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients". [[Nature (journal).
36. Aldinger KA. (2013). "Cerebellar and posterior fossa malformations in patients with autism-associated chromosome 22q13 terminal deletion". [[Am J Med Genet A]].
37. Giza J. (2010). "Behavioral and cerebellar transmission deficits in mice lacking the autism-linked gene islet brain-2.". J. Neurosci..
38. "SULT4A1 Gene - GeneCards | ST4A1 Protein | ST4A1 Antibody".
39. "PARVB Gene - GeneCards | PARVB Protein | PARVB Antibody".
40. "UCSC Genome Browser Home".
41. "MPPED1 Gene - GeneCards | MPPD1 Protein | MPPD1 Antibody".
42. "CYB5R3 Gene - GeneCards | NB5R3 Protein | NB5R3 Antibody".
43. "FBLN1 Gene - GeneCards | FBLN1 Protein | FBLN1 Antibody".
44. "NUP50 Gene - GeneCards | NUP50 Protein | NUP50 Antibody".
45. "KIAA0930 Gene - GeneCards | K0930 Protein | K0930 Antibody".
46. "SHISAL1 Gene - GeneCards | SHSL1 Protein | SHSL1 Antibody".
47. "TRMU Gene - GeneCards | MTU1 Protein | MTU1 Antibody".
48. "WNT7B Gene - GeneCards | WNT7B Protein | WNT7B Antibody".
49. "ATXN10 Gene - GeneCards | ATX10 Protein | ATX10 Antibody".
50. Sarasua SM. (2014). "Clinical and genomic evaluation of 201 patients with Phelan–McDermid syndrome.". [[Human Genetics (journal).
51. "UCSC Genome Browser Home".
52. "Human Gene Module".
53. (2012). "Mitochondrial Dysfunction in Pten Haplo-Insufficient Mice with Social Deficits and Repetitive Behavior: Interplay between Pten and p53.". [[PLoS ONE]].
54. (2015). "Low load for disruptive mutations in autism genes and their biased transmission.". [[PNAS.
55. (2012). "Loci nominally associated with autism from genome-wide analysis show enrichment of brain expression quantitative trait loci but not lymphoblastoid cell line expression quantitative trait loci". [[Molecular Autism]].
56. [https://human-phenotype-ontology.github.io/ Home. Human Phenotype Ontology]
57. "OMIM - Online Mendelian Inheritance in Man".
58. (2013-05-01). "Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions". Genetics in Medicine.
59. (2010-11-01). "Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities". Genetics in Medicine.
60. (2011-04-01). "Clinical utility gene card for: Deletion 22q13 syndrome". European Journal of Human Genetics.
61. (2011-01-01). "A unique presentation of 22q13 deletion syndrome: multicystic kidney, orofacial clefting, and Wilms' tumor". Clinical Dysmorphology.
62. (2005-08-30). "Molecular and phenotypic characterization of ring chromosome 22". American Journal of Medical Genetics Part A.
63. (2010-03-01). "22q13.3 deletion syndrome: clinical and molecular analysis using array CGH". American Journal of Medical Genetics Part A.
64. https://pmsf.org/
65. (2007-01-01). "Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders". Nature Genetics.
66. (2015-08-27). "Autism spectrum disorder in Phelan-McDermid syndrome: initial characterization and genotype–phenotype correlations". Orphanet Journal of Rare Diseases.
67. (2013-03-01). "Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders". European Journal of Human Genetics.
68. (1985-08-01). "A familial pericentric inversion of chromosome 22 with a recombinant subject illustrating a 'pure' partial monosomy syndrome.". Journal of Medical Genetics.
69. (2001-08-01). "Disruption of the ProSAP2 gene in a t(12;22)(q24.1;q13.3) is associated with the 22q13.3 deletion syndrome". American Journal of Human Genetics.
70. (2002-05-01). "FISH-mapping of a 100-kb terminal 22q13 deletion". Human Genetics.
71. (2003-08-01). "Molecular characterisation of the 22q13 deletion syndrome supports the role of haploinsufficiency of SHANK3/PROSAP2 in the major neurological symptoms". Journal of Medical Genetics.
72. (2008). "Interstitial 22q13 deletions: genes other than SHANK3 have major effects on cognitive and language development.". European Journal of Human Genetics.