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American Journal of Medical Part C (Seminars in ) 145C:393–398 (2007) ARTICLE

22q13.3 : A Recognizable Malformation Syndrome Associated With Marked Speech and Language Delay

KRISTINA CUSMANO-OZOG,* MELANIE A. MANNING, AND H. EUGENE HOYME

The 22q13.3 deletion syndrome is a recognizable malformation syndrome associated with developmental delay, , delayed or absent speech, autistic-like behavior, normal to accelerated growth and dysmorphic facies. The prevalence of this disorder is unknown, but it is likely under-diagnosed. Age at diagnosis has varied widely, from cases diagnosed prenatally to 46 years. Males and females are equally affected. The distal 22q deletion can be detected occasionally by routine or high resolution analysis; however, the majority of cases are detected by FISH analysis, associated with deletion of the ARSA (control) probe when performing a FISH analysis for the velocardiofacial syndrome (del 22q11.2). The 22q13.3 deletion syndrome can accompany a simple chromosome deletion, an unbalanced translocation, or a . Primary care , in addition to numerous specialists, play an important role in caring for patients with this disorder. Although the dysmorphic features observed in this condition are nonspecific, it is an important consideration in the differential diagnosis of children with developmental delay, hypotonia, marked speech and language disability, autistic-like features, multiple minor anomalies, and normal growth and head circumference. ß 2007 Wiley-Liss, Inc.

KEY WORDS: deletion 22q13.3; terminal 22q deletion syndrome; chromosome anomaly; dysmorphology; ; speech and language delay; developmental disabilities How to cite this article: Cusmano-Ozog K, Manning MA, Hoyme HE. 2007. 22q13.3 deletion syndrome: A recognizable malformation syndrome associated with marked speech and language delay. Am J Med Genet Part C Semin Med Genet 145C:393–398.

INTRODUCTION terminal deletion of 22q. No such behavior, normal to accelerated growth deletion was identified in a study of a and head circumference, and dysmor- Cryptic subtelomeric chromosome control population of normal individu- phic facial features. The prevalence of rearrangements account for 6–10% of als. Since that time, a number of reports this condition is unknown, but it is likely cases of idiopathic of mental retardation. of this disorder have been published, and under-diagnosed. Age at diagnosis has In 1995, Flint et al. [1995] evaluated 99 the pattern of malformation associated patients with idiopathic mental retarda- with this finding has been delineated. tion for subtelomeric chromosomal Patients with terminal deletions of rearrangements and identified three 22q share a common , includ- individuals with . Two of Patients with terminal ing developmental delay, hypotonia, these patients were noted to have a delayed or absent speech, autistic-like deletions of 22q share a common phenotype, including developmental delay, Kristina Cusmano-Ozog, M.D., is a Senior Medical Genetics Resident in the Stanford UCSF Medical Genetics Program. Her research interests include inborn errors of metabolism and the hypotonia, delayed or absent clinical delineation of malformation . Melanie A. Manning, M.D., is a Clinical Assistant Professor of and at speech, autistic-like behavior, Stanford University School of . Dr. Manning serves as the Associate Director of the Clinical Laboratory at Stanford University Medical Center. She has a longstanding normal to accelerated growth interest in clinical cytogenetics and in the deletion 22q13.3 syndrome in particular. and head circumference, and H. Eugene Hoyme, M.D., is currently Professor and Chairman of the Department of Pediatrics at the Sanford School of Medicine of the University of South Dakota and Pediatrician-in-Chief of dysmorphic facial features. The Sanford Children’s Hospital in Sioux Falls, SD. Dr. Hoyme is a dysmorphologist with interests in the clinical delineation of malformation syndromes, , the fetal alcohol syndrome and prevalence of this condition . *Correspondence to: Kristina Cusmano-Ozog, M.D., Division of Medical Genetics, H-315, is unknown, but it is likely Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305-5208. E-mail: [email protected] under-diagnosed. DOI 10.1002/ajmg.c.30155

ß 2007 Wiley-Liss, Inc. 394 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c ARTICLE varied widely, from cases diagnosed deletion 22q13.3 has been identified protein 2, ProSAP2 prenatally to 46 years. Males and females because he or she was used as a control are equally affected [Manning et al., 2004]. for VCF FISH analysis or was being (SHANK3), was a good The purpose of this report is to evaluated for VCF by FISH analysis. candidate gene for the 22q13.3 review the existing literature regarding [Phelan et al., 2001; Havens et al., 2004; deletion 22q13.3 syndrome and to Manning et al., 2004; Phelan, 2005]. deletion syndrome, as it is suggest clinical management and genetic preferentially expressed in the counseling guidelines for affected indi- MOLECULAR cerebral cortex and cerebellum viduals and their families. CHARACTERIZATION and it encodes a scaffolding Nesslinger et al. [1994] characterized the CYTOGENETIC protein involved in the critical area for the del 22q13.3 syn- DESCRIPTION drome in seven patients with deletions postsynaptic density of 22q13.3 deletions result from the loss of ranging in size from 5 to 8 Mb, demon- excitatory synapses. genetic material from the terminus of strating that the critical area for the the long arm of one copy of chromo- deletion breakpoint occurred between some 22. Monosomy 22q13.3 can D22S92 and D22S94. Wonget al. [1997] boy with developmental delay, severe accompany a simple deletion, an unbal- subsequently reduced the critical area speech delay, hypotonia and dysmorphic anced translocation, or a ring chromo- to an area of 130 kb. Anderlid et al. features. Chromosome analysis showed some. About 75% of all cases are simple [2002] further refined the area to 100 kb, a translocation; 46,XY,t(12;22)(q24.1; deletions, with the remaining 25% of which contains three genes, ProSAP2 q13.3). Sequence analysis identified the cases resulting from structural rearrange- (SHANK3), ACR and RABL2B. breakpoint on 22 at position 296489/ ments of the affected segment. Deletion Schroder et al. [1998] compared 296494, within 21 of the human 22q13.3 is usually a de novo finding; cytogenetic findings with molecular data homologue of the rat ProSAP2 (Shank-3 however, approximately 20% of cases are obtained by FISH and an array of and SPANK-2). The ProSAP2 gene familial, in which a child receives an bacterial artificial chromosome (BAC) spans a 60-kb region on chromosome unbalanced chromosome complement recombinants. Clinical features shared 22. It has 22 and lies between from a parent who carries a balanced by these three individuals included ARSA and acrosin. Northern blot reciprocal translocation. cases normal to accelerated growth, hypoto- analysis of human tissues showed a 3- have also been described. The deletion nia, and delayed psychomotor and kb band expressed in heart, kidney, liver is usually terminal and includes the speech development. Hearing loss was and placenta and two transcripts (7- and telomere; however, interstitial deletions detected in three patients and kidney 8-kb) seen in brain. have been demonstrated in which abnormalities were noted in two. One Wilson et al. [2003] further charac- the telomere is spared. The deletion had a deletion with the breakpoint terized the role of SHANK3 in 22q13.3 occasionally can be detected by high between D22S40 and D22S97. Another deletion syndrome by evaluating 56 resolution chromosome analysis, but had a 38 cM deletion with the break- patients. The size of the deletion varied the majority of cases are detected point between D22S92 and D22S95. from 130 kb to over 9 Mb, and all cases by fluorescence in situ hybridization The last had a 26 cM deletion with the that could be analyzed (45/56) demon- (FISH) analysis using either the arylsul- breakpoint between D22S97 and strated a deletion of an area containing fatase A (ARSA) or D22S1726 (subtelo- D22S94. These breakpoints occurred SHANK3. Nine of these patients meric) probe. Use of both probes is within the critical area reported by previously had been reported [Zwaigen- recommended, since distal deletions Nesslinger. baum et al., 1990; Phelan et al., 1992; may be missed with the ARSA probe Bonaglia et al. [2001] suggested that Powell et al., 1993; Nesslinger et al., alone, and interstitial deletions may be proline rich synapse associated protein 2, 1994; Feldman et al., 1995; Flint et al., missed with the D22S1726 probe alone. ProSAP2 (SHANK3), was a good can- 1995; Eydoux et al., 1996; Wong et al., Using both probes detects 100% of cases. didate gene for the 22q13.3 deletion 1997]. Eleven patients exhibited unbal- Comparative genomic hybridization syndrome, as it is preferentially expressed anced translocations, three of which (CGH) can be used to not only identify in the cerebral cortex and cerebellum were inherited. One was mosaic and the deletion in suspected cases, but and it encodes a scaffolding protein one had a complex chromosome rear- also to further characterize the size of involved in the postsynaptic density of rangement involving 21 the deletion. Although the deletion excitatory synapses. They identified a and 22. Parental origin of the deletion may be intentionally identified, it is was determined in 39 cases; 27 were frequently discovered serendipitously paternal and 12 maternal. There was when the velocardiofacial syndrome Bonaglia et al. suggested that a statistically significant correlation (del 22q11.2) is suspected. On several between the size of the deletion and occasions an affected individual with proline rich synapse associated the degree of developmental delay. ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c 395

Clinical features such as hypotonia shared a common phenotype of devel- toe . Luciani et al. [2003] showed increased severity or higher opmental delay, hypotonia, normal to documented 33 affected patients ranging incidence with larger deletions. Char- accelerated growth, severe expressive from 1 to 34 years of age, including one acterization of the SHANK3 gene by speech delay and minor facial dysmor- previously reported in the literature [De cDNA analysis and RT-PCR products phic features. The authors noted that the Mas et al., 2002]. Seventeen were demonstrated two exons (22 and 23) not individuals previously reported also females and 16 were males. Seventeen previously described. Exon 24 presum- shared some of the characteristics. exhibited a ring 22 chromosome, 12 had ably corresponds to exon 22 in the above Flint et al. [1995] discovered two a simple terminal deletion and 4 had an paper. There are a number of alternative cases of 22q13.3 deletion by screening unbalanced translocation, 1 of which products with an alternative splice site the subtelomeric regions of chromo- was inherited. The size of the deletion between exons 10 and 13 and three somes in individuals with mental retar- was variable, ranging from 160 kb to alternative 30 ends identified. Northern dation. One case was a 22-year-old 9 Mb. Parental studies revealed that the blot analysis revealed that the 8 kb female with facial dysmorphism and deletion was inherited from the father transcript, initially only seen in brain, is absent language. The other was a non- 74% of the time and from the mother also expressed in the heart. A 2 kb dysmorphic 12-year-old male with 26% of the time. Developmental delay, transcript was observed strongly in heart speech impairment who did not begin severe expressive speech delay and and weakly in liver and kidney. A 10 kb speaking until age 4. Wong et al. [1997] behavior disorders were observed in all transcript was strongly expressed in further characterized the deletion dis- patients. Hypotonia and large or dys- cerebellum and present at low levels in covered in the male patient first reported plastic ears were the next most common most tissue. The 7.5 and 8 kb transcripts by Flint. The deletion was found to span findings. were noted in a few showed moderate expression in all brain the terminal 130 kb of . individuals. Although not a universal tissue with lower expression in medulla Subsequently, a number of case finding, accelerated growth was seen in spinal cord. Genotype–phenotype cor- reports and small series of affected those with deletions or translocations, relations were noted in these individuals. patients further delineated a recogniz- and growth restriction was seen in those Bonaglia et al. [2006] presented an able del 22q13.3 syndrome [Doheny with a ring chromosome. There was a additional two cases, one previously et al., 1997; Slavotineket al., 1997; Fujita positive correlation between the severity reported by Anderlid et al. [2002], that et al., 2000; Praphanphoj et al., 2000; of features and the size of deletion. share the same breakpoint as the indi- Prasad et al., 2000; Anderlid et al., 2002; Manning et al. [2004] reported on 11 vidual described by Wong et al. [1997]. Barakat et al., 2004; Lindquist et al., cases, 10 female and 1 male, ranging in FISH analysis with the n85a3 probe 2005; Tabolacci et al., 2005; Babineau age from 5 months to 46 years. All confirmed the deletion. The breakpoint et al., 2006]. In addition, several larger patients exhibited delayed development was localized to the proximal part of series of affected individuals have with severe expressive speech and lan- n85a3, which contains the SHANK3 delineated a widely variable disorder in guage delay and varying degrees of gene. The size of the deletion was which normal to accelerated growth, hypotonia. Six individuals had autistic- estimated to be 100 kb. The breakpoints hypotonia and marked speech and like behavior. Dysmorphic features occurred within 15 bp of each other, language impairment are the most included epicanthal folds, full supra- inside a short simple repeat located reproducible features. Phelan et al. orbital ridges, large cupped ears, under- between exons 8 and 9 of SHANK3. [2001] reported on 37 individuals, 17 developed philtrum and loss of cupid’s males and 20 females aged 12 months to bow. The deletion was microscopically 26 years. Five of these had been visible in six patients, five of whom REVIEW OF CASES FROM previously described [Nesslinger et al., had inherited an unbalanced trans- THE LITERATURE 1994; Doheny et al., 1997]. Twenty- location. The deletion was detected by In 1994, Nesslinger et al. [1994] nine individuals were noted to have FISH analysis in five patients; four of reported on seven cases of deletion terminal deletions and 8 had unbalanced these were detected serendipitously 22q13.3 detected by chromosome anal- translocations. Of these eight, four were during a FISH study to evaluate for del ysis. Although the deletion had been de novo and four were inherited, three 22q11.2. reported previously [Watt et al., 1985; maternal and one paternal. Age at Several authors have documented Herman et al., 1988; Kirshenbaum et al., the time of diagnosis varied from prenatal diagnosis of the 22q13.3 syn- 1988; Romain et al., 1990; Narahara prenatal to 20 years. Common features drome by genetic and et al., 1992; Phelan et al., 1992], these included developmental delay, marked fetal and FISH studies [Phelan authors were the first to suggest that speech and language delay, hypotonia et al., 2001; Chen et al., 2003]. individuals with this microdeletion share and normal to accelerated growth. A similar phenotype has been a common phenotype. In their study, Dysmorphic features included dolicho- documented in a large number of which included the patient of Phelan cephaly, epicanthal folds, ptosis, prom- patients with . et al. [1992], there were four males and inent or dysplastic ears, pointed chin, Battini et al. [2004] presented a patient three females, ages 2–5 years. They all large and fleshy or broad hands, and 2–3 with a ring 22 chromosome who 396 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c ARTICLE demonstrated hypotonia, speech impair- between the size of the deletion and the Hypotonia can be identified in the ment, mental retardation, unusual severity of symptoms and signs. neonatal period, associated with poor behavior and dysmorphic features. FISH head control, weak cry and poor suck. analysis confirmed a distal deletion Developmental delay is usually in the SUMMARY OF CLINICAL approximately 2.5 Mb in size. moderate to severe range, and primarily FINDINGS Delcan et al. [2004] reported on a affects the major milestones. For exam- case of ring chromosome 22 with a Patients with terminal deletions of 22q ple, the average age for rolling over is deletion of 22q13.3 identified by amnio- share a common phenotype, including 8 months (compared to 4–5 months), centesis in a 16-week gestation fetus. developmental delay,hypotonia, delayed the average age for crawling is 16 months Chromosome analysis revealed the ring or absent speech, autistic-like behavior, and the average age for walking is 22 chromosome, and FISH analysis normal to accelerated growth and dys- three years (compared to 12 months). demonstrated the deletion of 22q13.3. morphic facial features. As above, several Hypotonia contributes to the delay in The pregnancy was terminated and authors have described the phenotype in obtaining these milestones. autopsy revealed agenesis of the corpus detail [Phelan et al., 2001; Luciani et al., Speech delay or severe language callosum, septum pellucidum, and for- 2003; Manning et al., 2004; Lindquist impairment with little to no speech is nix as well as absence of the optic chiasm. et al., 2005]. Clinical features are common. Some individuals may begin Jeffries et al. [2005] collected data on 35 summarized in Table I, and Figures 1 to babble and develop limited vocabu- individuals with a ring 22 chromosome. and 2 depict affected children with lary before there is loss of speech. Most Thirty-one families participated (13 deletion 22q13.3. patients eventually are able to commu- from the UK, 10 USA, 3 Australia, 2 nicate by other means, such as a France, 1 Belgium, 1 Italy, 1 South communication board. Receptive lan- Africa). The mean age was 10 years. The guage skills exceed expressive language majority demonstrated weight and in this condition, and individuals are TABLE I. Clinical Features of height appropriate for their age. Two often able to followone-step commands. Terminal 22q Deletion Syndrome had growth failure and two had accel- Mental retardation is frequently erated growth. Impairment was noted in Number observed, with the majority of individ- all areas of development. Evaluation for Feature reported uals in the moderate to severe range. In autistic traits by the SCQ revealed that addition to mental retardation, most Total cases reviewed 107 two-thirds scored above the cut-off, and patients meet diagnostic criteria for Perinatal evaluation for ADHD by the SDQ autism and demonstrate behavioral Te r m 1 8 revealed one-third scored above the issues including: poor eye contact, AGA 26 cut-off. Dysmorphic features were stereotypical behaviors, self-stimulation, Growth noted, but were not consistent. The repetitive chewing behaviors, , Normal/accelerated 95 origin of the ring was determined in 28 biting, hitting and abnormal sleep pat- Neurodevelopment individuals; 16 were paternal and 12 terns. Increased tolerance to pain and Developmental delay 105 maternal. other behavioral abnormalities, such as Delayed/absent 103 Although the majority of patients inappropriate chewing of clothes or speech with del 22q13.3 have been detected by toys, has also been described. Hypotonia 92 FISH analysis, Koolen et al. [2005] Dysmorphic features commonly Autistic behaviors/ 47 characterized nine patients using chro- exhibited by affected individuals include chewing mosome specific array-based CGH. , abnormal ears, pointed Regression 5 Three cases had been previously pub- chin, ptosis, epicanthal folds, 2/3 toe Seizures 25 lished. The deletions were initially syndactyly, dysplastic/hypoplastic toe- High pain threshold 33 identified by chromosome analysis in nails, large hands, and a Lack of perspiration 19 two and FISH analysis in seven. The two tendency to become overheated with Craniofacial identified by chromosome analysis were decreased perspiration. Abnormalities in Epicanthal folds 32 confirmed by FISH analysis. One indi- growth have been observed. At birth, Large/dysplastic ears 58 vidual had a de novo translocation. The patients are appropriate for gestational Pointed chin 29 deletions ranged in size from 8.4 to age; however, as they continue to grow, Dolichocephaly 32 3.3 Mb. One individual with a 3.9 Mb they are often described as being tall and Ptosis 25 deletion also had a 2.0 Mb duplication. thin and some may have large head size. Extremities There were five females and four males. There have been a few reports of intra- 2–3 toe syndactyly 25 Developmental delay and severe speech uterine growth restriction and failure to Abnormal nails 39 delay to absent speech were noted in all thrive. Large hands 35 individuals. Hypotonia was noted in Symptoms and signs in essentially most of them. There was no correlation every organ system have been reported. ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c 397

ing vision or hearing issues that may affect development. Speech and lan- guage evaluations and speech are needed to ensure maximum communi- cation potential. Dental evaluation is

Routine ophthalmologic and audiologic evaluations are needed to assess for and treat confounding vision or hearing issues that may affect Figure 1. This girl demonstrates periorbital fullness, anteverted nares, smooth development. Speech and philtrum with absence of cupid’s bow, downturned mouth and prominent cupped ears (reprinted with permission from: Manning et al. [2004], Pediatrics 114:451–457). language evaluations and [Color figure can be viewed in the online issue, which is available at www.interscience. wiley.com.] speech therapy are needed to ensure maximum communication potential. Some individuals have been noted to MANAGEMENT have hearing loss and/or visual impair- Primary care physicians play an impor- ment. Dental problems, such as maloc- needed on a regular basis, especially if tant role in caring for patients with the clusion, are common. A few individuals there are problems such as . del 22q13.3 syndrome. Neurologists and have demonstrated neurological find- Finally, evaluation for malformations of physical therapists can assist with treating ings, including seizures and abnormal other organ systems, including the hypotonia and neurologists can manage deep tendon reflexes or abnormal find- cardiac, gastrointestinal, and genitouri- associated disorders. Infant ings on magnetic resonance imaging of nary systems is necessary, and appropri- development specialists and child psy- the brain. Congenital heart defects, such ate follow-up for specific abnormalities chiatrists can evaluate for developmental as and ventric- identified is essential. delay and autistic-features and provide ular septal defect, have been reported on medications as needed to treat specific occasion. Gastroesophageal reflux and behavior problems. Routine ophthal- cyclic vomiting have been documented SUMMARY mologic and audiologic evaluations are in a few patients, and vesicoureteral needed to assess for and treat confound- Cryptic subtelomeric chromosome re- reflux has also been described. arrangements account for 6–10% of idiopathic cases of mental retardation, of which deletions of 22q13.3 represent a significant proportion. The deletion can be detected occasionally by chromo- some analysis; however, the majority of cases are detected by FISH analysis (either targeted or by screening subtelo- meres) or by array CGH. The 22q13.3 deletion can accompany a simple dele- tion, unbalanced translocation, or ring chromosome. Patients with terminal deletions of 22q share a common phenotype, including developmental delay, hypotonia, markedly delayed or absent speech, autistic-like behavior, normal to accelerated growth and non- Figure 2. Affected boy with periorbital fullness, ptosis, large ears, anteverted nares, specific dysmorphic facial features. A downturned mouth, and an altered ‘‘hockey stick’’ upper palmar crease. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.] careful review of the literature indicates that all patients with hypotonia, marked 398 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c ARTICLE expressive speech and language delay, Flint J, Wilkie AO, Buckle VJ, Winter RM, Phelan MC. 2005. 22q13.3 deletion syndrome. nonspecific dysmorphic features and Holland AJ, McDermid HE. 1995. The In: GeneReviews. 15 Jun 2006 (http:// detection of subtelomeric chromosomal www.geneclinics.org/query?dz¼22q13.31). normal should be screened rearrangements in idiopathic mental retar- Phelan MC, Thomas GR, Saul RA, Rogers RC, for this common disorder. dation. Nat Genet 9:132–140. Taylor HA, Wenger DA, McDermid HE. Fujita Y, Mochizuki D, Mori Y, Nakamoto N, 1992. Cytogenetic, biochemical, and mole- Kobayashi M, Omi K, Kodama H, Yana- cular analyses of a 22q13 deletion. Am J REFERENCES gawa Y, Abe T, Tsuzuku T, Yamanouchi Y, Med Genet 43:872–876. Takano T. 2000. Girl with accelerated Phelan MC, Rogers RC, Saul RA, Stapleton Anderlid BM, Schoumans J, Annere´n G, Tapia- growth, hearing loss, inner ear anomalies, GA, Sweet K, McDermid H, Shaw SR, Paez I, Dumanski J, Blennow E, Nordensk- delayed myelination of the brain, and Claytor J, Willis J, Kelly DP. 2001. 22q13 jo¨ld M. 2002. FISH-mapping of a 100-kb del(22)(q13.1q13.2). Am J Med Genet 92: deletion syndrome. Am J Med Genet 101: terminal 22q13 deletion. Hum Genet 110: 195–199. 91–99. 439–443. Havens JM, Visootsak J, Phelan MC, Graham Powell BR, Budden SS, Buist NR. 1993. Babineau T, Wilson HL, Dawson AJ, Chodirker JMJr. 2004. : An Dominantly inherited , BN, Der Kaloustian VM, Demczuk S, update and review for the primary pedia- muscle weakness, and myoliposis: A carni- McDermid HE. 2006. Unusual dicentric trician. Clin Pediatr (Phila) 43:43–53. tine-deficient myopathy within the spec- chromosome 22 associated with a 22q13 Herman GE, Greenberg F, Ledbetter DH. 1988. trum of the Ruvalcaba-Myhre-Smith deletion. Am J Med Genet Part A 140A: Multiple congenital anomaly/mental retar- syndrome. J Pediatr 123:70–75. 2819–2823. dation (MCA/MR) syndrome with Gold- Praphanphoj V, Goodman BK, Thomas GH, Barakat AJ, Pearl PL, Acosta MT, Runkle BP. enhar complex due to a terminal del(22q). Raymond GV. 2000. Cryptic subtelomeric 2004. 22q13 deletion syndrome with central Am J Med Genet 29:909–915. translocations in the 22q13 deletion syn- diabetes insipidus: A previously unreported Jeffries AR, Curran S, Elmslie F, Sharma A, drome. J Med Genet 37:58–61. association. Clin Dysmorphol 13:191– Wenger S, Hummel M, Powell J. 2005. Prasad C, Prasad AN, Chodirker BN, Lee C, 194. Molecular and phenotypic characterization Dawson AK, Jocelyn LJ, Chudley AE. 2000. Battini R, Battaglia A, Bertini V, Cioni G, Parrini of ring chromosome 22. Am J Med Genet Genetic evaluation of pervasive develop- B, Rapalini E, Simi P, Tinelli F, Valetto A. Part A 137A:139–147. mental disorders: The terminal 22q13 2004. Characterization of the phenotype Kirshenbaum G, Chmura M, Rhone DP. 1988. deletion syndrome may represent a recog- and definition of the deletion in a new Long arm deletion of chromosome 22. J nizable phenotype. Clin Genet 57:103–109. patient with ring chromosome 22. Am J Med Genet 25:780. Romain DR, Goldsmith J, Cairney H, Colum- Med Genet Part A 130A:196–199. Koolen DA, Reardon W,Rosser EM, Lacombe D, bano-Green LM, Smythe RH, Parfitt RG. Bonaglia MC, Giorda R, Borgatti R, Felisari G, Hurst JA, Law CJ, Bongers EM, van 1990. Partial monosomy for chromosome Gagliardi C, Selicorni A, Zuffardi O. 2001. Ravenswaaij-Arts CM, Leisink MA, van 22 in a patient with del(22)(pter----q13.1:: Disruption of the ProSAP2 gene in a Kessel AG, Veltman JA, de Vries BB. 2005. q13.33----qter). J Med Genet 27:588–589. t(12;22)(q24.1;q13.3) is associated with the Molecular characterisation of patients with Schroder K, Schuffenhauer S, Seidel H, Bartsch 22q13.3 deletion syndrome. Am J Hum subtelomeric 22q abnormalities using chro- O, Blin N, Hinkel GK, Schmitt H. 1998. Genet 69:261–268. mosome specific array-based comparative Deletion mapping by FISH with BACs in Bonaglia MC, Giorda R, Mani E, Aceti G, genomic hybridisation. Eur J Hum Genet patients with partial monosomy 22q13. Anderlid BM, Baroncini A, Pramparo T, 13:1019–1024. Hum Genet 102:557–561. Zuffardi O. 2006. Identification of a recur- Lindquist SG, Kirchhoff M, Lundsteen C, Peder- Slavotinek A, Maher E, Gregory P,Rowlandson P, rent breakpoint within the SHANK3 gene sen W, Erichsen G, Kristensen K, Lillquist Huson SM. 1997. The phenotypic effects of in the 22q13.3 deletion syndrome. J Med K, Smedegaard HH, Skov L, Tommerup N, chromosome rearrangement involving Genet 43:822–828. Brøndum-Nielsen K. 2005. Further delin- bands 7q21.3 and 22q13.3. J Med Genet Chen CP, Lin SP, Chern SR, Shih SL, Lee CC, eation of the 22q13 deletion syndrome. Clin 34:857–861. Wang W, Liao YW. 2003. Perinatal findings Dysmorphol 14:55–60. Tabolacci E, Zollino M, Lecce R, Sangiorgi E, and molecular cytogenetic analysis of tri- Luciani JJ, de Mas P, Depetris D, Mignon-Ravix Gurrieri F, Leuzzi V, Opitz JM, Neri G. somy 16q and 22q13.3 deletion. Prenat C, Bottani A, Prieur M, Jonveaux P, 2005. Two brothers with 22q13 deletion Diagn 23:504–508. Philippe A, Bourrouillou G, de Martinville syndrome and features suggestive of the De Mas P, Chassaing N, Chaix Y, Vincent MC, B, Delobel B, Vallee L, Croquette MF, Clark-Baraitser syndrome. Clin Dysmor- Julia S, Bourrouillou G, Calvas P, Bieth E. Mattei MG. 2003. Telomeric 22q13 dele- phol 14:127–132. 2002. Molecular characterisation of a ring tions resulting from rings, simple deletions, Watt JL, Olson IA, Johnston AW, Ross HS, chromosome 22 in a patient with severe and translocations: Cytogenetic, molecular, Couzin DA, Stephen GS. 1985. A familial language delay: A contribution to the and clinical analyses of 32 new observations. pericentric inversion of chromosome 22 refinement of the subtelomeric 22q deletion J Med Genet 40:690–696. with a recombinant subject illustrating a syndrome. J Med Genet 39:e17. Manning MA, Cassidy SB, Clericuzio C, Cherry ’pure’ partial monosomy syndrome. J Med Delcan J, Orera M, Linares R, Saavedra D, AM, Schwartz S, Hudgins L, Enns GM, Genet 22:283–287. Palomar A. 2004. A case of ring chromo- Hoyme HE. 2004. Terminal 22q deletion Wilson HL, Wong AC, Shaw SR, Tse WY, some 22 with deletion of the 22q13.3 region syndrome: A newly recognized cause of Stapleton GA, Phelan MC, Hu S, Marshall J, associated with agenesis of the corpus speech and language disability in the McDermid HE. 2003. Molecular character- callosum, fornix and septum pellucidum. . Pediatrics 114:451– isation of the 22q13 deletion syndrome Prenat Diagn 24:635–637. 457. supports the role of haploinsufficiency of Doheny KF, McDermid HE, Harum K, Thomas Narahara K, Takahashi Y, Murakami M, Tsuji K, SHANK3/PROSAP2 in the major neuro- GH, Raymond GV. 1997. Cryptic terminal Yokoyama Y, Murakami R, Ninomiya S, logical symptoms. J Med Genet 40:575– rearrangement of chromosome 22q13.32 Seino Y. 1992. Terminal 22q deletion 584. detected by FISH in two unrelated patients. associated with a partial deficiency of Wong AC, Ning Y, Flint J, Clark K, Dumanski JP, J Med Genet 34:640–644. arylsulphatase Am J Med Genet 29:432– Ledbetter DH, McDermid HE. 1997. Eydoux P, Sanderson D, Treacy E, Scriver C, 433. Molecular characterization of a 130-kb Teebi AS. 1996. HHH-like syndrome and Nesslinger NJ, Gorski JL, Kurczynski TW,Shapira terminal microdeletion at 22q in a child dysmorphic features associated with 22q SK, Siegel-Bartelt J, Dumanski JP, Cullen with mild mental retardation. Am J Hum deletion. Am J Hum Genet 59:A117. RFJr, French BN, McDermid HE. 1994. Genet 60:113–120. Feldman G, Wiktor A, Conard J, Van Dyke DL. Clinical, cytogenetic, and molecular char- Zwaigenbaum L, Siegel-Bartelt J, Teshima I, Ho 1995. Identification by FISH of a acterization of seven patients with deletions C. 1990. Two patients with 22q13.3 dele- del(22)(q13.3) in a patient with de novo of chromosome 22q13.3. Am J Hum Genet tions have similar facies and developmental 22qs. Am J Hum Genet 57:A113. 54:464–472. patterns. Am J Hum Genet 47:A45.