Xp11.2 duplication

Information on the clinical symptoms and features is taken from the Human Phenotype Ontology database{{Cite web|url=https://human-phenotype-ontology.github.io/|title=Home|website=Human Phenotype Ontology|access-date=2018-02-28}} and the Unique database. All affected individuals needn't show all the symptoms. Some of the most noted features are:

• Intellectual and Learning Disabilities
• Speech delay
• Early puberty
• Significant weight and height problems
• Lower-extremity anomalies (anomalies of the legs and/ or feet)
• Epileptic Seizures
• Unusual pattern of EEG with centro-temporal focal spike waves in children
• Minor facial features

Among people who need support with their learning, at least 3% are believed to carry the duplication. It is noted that affected members of the same family with the same Xp11.2 microduplication generally have similar learning profiles. Children with small duplications of 0.5-1.3 Mb seem to have a mild learning difficulty, while others with the typical duplication of around 4.5 Mb generally have a borderline, mild or moderate learning disability. An extreme case with a very large duplication of 55 Mb has shown to have a severe intellectual disability.{{cite journal | vauthors = Nizon M, Andrieux J, Rooryck C, de Blois MC, Bourel-Ponchel E, Bourgois B, Boute O, David A, Delobel B, Duban-Bedu B, Giuliano F, Goldenberg A, Grotto S, Héron D, Karmous-Benailly H, Keren B, Lacombe D, Lapierre JM, Le Caignec C, Le Galloudec E, Le Merrer M, Le Moing AG, Mathieu-Dramard M, Nusbaum S, Pichon O, Pinson L, Raoul O, Rio M, Romana S, Roubertie A, Colleaux L, Turleau C, Vekemans M, Nabbout R, Malan V | display-authors = 6 | title = Phenotype-genotype correlations in 17 new patients with an Xp11.23p11.22 microduplication and review of the literature | journal = American Journal of Medical Genetics. Part A | volume = 167A | issue = 1 | pages = 111–22 | date = January 2015 | pmid = 25425167 | doi = 10.1002/ajmg.a.36807 | s2cid = 32958511 }}

Speech is very commonly affected and usually the first sign. Both speech and comprehension seem to be affected, to various degrees of extent. Low facial muscle tone underlies difficulty in making certain sounds of speech. Nasal or hoarse voice are also observed. Babies are known to be unable to suck from breast in their infancy due to weak facial muscles.

Early puberty occurs in 80% of the affected children or adults, with girls starting their menstrual cycles as early as age 9 and boys showing signs of puberty at age 8.5. One boy from Unique had completed puberty by age 13.

Affected children show tendency to be overweight. This might indicate metabolism issues.

Anomalies of lower limbs or feet are common in people with an Xp11.2 duplication, affecting about 71% cases. Features include flat feet, arched feet (pes cavus), clubfoot (talipes), narrow feet, webbed or joined toes/fingers (syndactyly), 5th finger clinodactyly, 5th toe hypoplasia, and tapering fingers.{{cite journal | vauthors = Firth HV, Richards SM, Bevan AP, Clayton S, Corpas M, Rajan D, Van Vooren S, Moreau Y, Pettett RM, Carter NP | title = DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources | journal = American Journal of Human Genetics | volume = 84 | issue = 4 | pages = 524–33 | date = April 2009 | pmid = 19344873 | doi = 10.1016/j.ajhg.2009.03.010 | pmc = 2667985 }}

A typical pattern of electrical activity in the brain of affected children, described as ‘subclinical seizures’ has been noted. A peculiar electroencephalographic pattern characterized by rolandic-like spikes and/or continuous spike wave during slow sleep (CSWS), also called centro-temporal focal spike, exists in childhood.

The common unusual features include a short or flat groove between the nose and upper lip (philtrum), a large, high or deep nasal bridge, bushy eyebrows and/or uni-brow (synophrys), and thin lips.

Using array-based Comparative Genomic Hybridization (aCGH) to screen 2,400 individuals with isolated or syndromic mental retardation for copy number variation, Giorda et al. (2009) identified 8 (0.33%) unrelated individuals, 2 males and 6 females, with a microduplication at chromosome Xp11.23-p11.22. The rearrangement was familial in 3 patients. A female patient shared a 4.5-Mb duplication with her affected mother and sister, and an unrelated male patient shared a 4.5-Mb duplication with his affected mother and sister. A third unrelated male inherited a smaller 0.8-Mb duplication from his unaffected mother. Three additional individuals had de novo 4.5-Mb duplications, and 2 more had partially overlapping de novo 6.0- and 9.2-Mb duplications. Paternal origin of the duplication was demonstrated in all de novo female cases. Six affected females had selective inactivation of the normal X chromosome, whereas 3 had random X inactivation. Breakpoints could be identified in 8 individuals. The recurrent duplication was flanked distally by a segmental duplication (D-REP at 47.8-48.2 Mb) containing a cluster of genes and pseudogenes of the synovial sarcoma X breakpoint (SSX) and proximally by a complex repeat (P-REP at 52.1-53.1 Mb) rich in SSX, melanoma antigen and X antigen (XAGE) genes. Sequence analysis of the junctions demonstrated that the recurrent 4.5-Mb duplications were mediated by non-allelic homologous recombination (NAHR) or Alu-mediated recombination. The majority of these recombinations occurred between flanking complex segmental duplications. Region of duplication and copy number variation can be further confirmed by Fluorescence In-Situ Hybridization (FISH) and PCR.

The duplication at Xp11.2, especially the Xp11.22-11.23 region is syndromic and is implicated in X-linked mental retardation.{{OMIM|300705|Chromosome Xp11.22 Duplication Syndrome}} The chromosomal duplication can be de novo or familial. Familial carriers of small duplication (<1 Mb) show X-linked recessive inheritance. All other affected individuals with larger duplication present dominant expression and comparable clinical phenotypes irrespective of sex, duplication size, and X-inactivation pattern.

Xp11.22 comprises approximately 5 Mb of DNA (chrX:49,800,001–54,800,000, hg19). A number of pathogenic deletions and duplications involving Xp11.22 have been described in individuals with developmental delay, intellectual disability and/or autism.{{cite journal | vauthors = Grau C, Starkovich M, Azamian MS, Xia F, Cheung SW, Evans P, Henderson A, Lalani SR, Scott DA | title = Xp11.22 deletions encompassing CENPVL1, CENPVL2, MAGED1 and GSPT2 as a cause of syndromic X-linked intellectual disability | journal = PLOS ONE | volume = 12 | issue = 4 | pages = e0175962 | date = 2017-04-17 | pmid = 28414775 | doi = 10.1371/journal.pone.0175962 | bibcode = 2017PLoSO..1275962G | pmc = 5393878 | doi-access = free }} These phenotypes have been attributed to changes in the copy number of several genes including HUWE1, KDM5C, IQSEC2, TSPYL2, SHROOM4, PHF8 and FAM120C.{{cite journal | vauthors = Orivoli S, Pavlidis E, Cantalupo G, Pezzella M, Zara F, Garavelli L, Pisani F, Piccolo B | title = Xp11.22 Microduplications Including HUWE1: Case Report and Literature Review | journal = Neuropediatrics | volume = 47 | issue = 1 | pages = 51–6 | date = January 2016 | pmid = 26587761 | doi = 10.1055/s-0035-1566233 | s2cid = 38240788 }}{{cite journal | vauthors = Moey C, Hinze SJ, Brueton L, Morton J, McMullan DJ, Kamien B, Barnett CP, Brunetti-Pierri N, Nicholl J, Gecz J, Shoubridge C | title = Xp11.2 microduplications including IQSEC2, TSPYL2 and KDM5C genes in patients with neurodevelopmental disorders | journal = European Journal of Human Genetics | volume = 24 | issue = 3 | pages = 373–80 | date = March 2016 | pmid = 26059843 | pmc = 4757771 | doi = 10.1038/ejhg.2015.123 }}

The HECT, UBA and WWE domain-containing protein 1 (HUWE1) is a HECT family ubiquitin ligase located on the X chromosome at Xp11.22 with growing genetic links to cancer{{cite journal | vauthors = Zhong Q, Gao W, Du F, Wang X | title = Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis | journal = Cell | volume = 121 | issue = 7 | pages = 1085–95 | date = July 2005 | pmid = 15989957 | doi = 10.1016/j.cell.2005.06.009 | doi-access = free }} and intellectual disability.{{cite journal | vauthors = Froyen G, Corbett M, Vandewalle J, Jarvela I, Lawrence O, Meldrum C, Bauters M, Govaerts K, Vandeleur L, Van Esch H, Chelly J, Sanlaville D, van Bokhoven H, Ropers HH, Laumonnier F, Ranieri E, Schwartz CE, Abidi F, Tarpey PS, Futreal PA, Whibley A, Raymond FL, Stratton MR, Fryns JP, Scott R, Peippo M, Sipponen M, Partington M, Mowat D, Field M, Hackett A, Marynen P, Turner G, Gécz J | display-authors = 6 | title = Submicroscopic duplications of the hydroxysteroid dehydrogenase HSD17B10 and the E3 ubiquitin ligase HUWE1 are associated with mental retardation | journal = American Journal of Human Genetics | volume = 82 | issue = 2 | pages = 432–43 | date = February 2008 | pmid = 18252223 | pmc = 2426915 | doi = 10.1016/j.ajhg.2007.11.002 }} Expression of the HUWE1 gene is found in several mouse tissues including cortex, hippocampus, tongue, eye, kidney, liver, adrenal gland, and fibroblasts.{{cite journal | vauthors = Froyen G, Belet S, Martinez F, Santos-Rebouças CB, Declercq M, Verbeeck J, Donckers L, Berland S, Mayo S, Rosello M, Pimentel MM, Fintelman-Rodrigues N, Hovland R, Rodrigues dos Santos S, Raymond FL, Bose T, Corbett MA, Sheffield L, van Ravenswaaij-Arts CM, Dijkhuizen T, Coutton C, Satre V, Siu V, Marynen P | display-authors = 6 | title = Copy-number gains of HUWE1 due to replication- and recombination-based rearrangements | journal = American Journal of Human Genetics | volume = 91 | issue = 2 | pages = 252–64 | date = August 2012 | pmid = 22840365 | pmc = 3415555 | doi = 10.1016/j.ajhg.2012.06.010 }} Increased copies of HUWE1 are associated with non-syndromic intellectual disability.{{cite journal | vauthors = Friez MJ, Brooks SS, Stevenson RE, Field M, Basehore MJ, Adès LC, Sebold C, McGee S, Saxon S, Skinner C, Craig ME, Murray L, Simensen RJ, Yap YY, Shaw MA, Gardner A, Corbett M, Kumar R, Bosshard M, van Loon B, Tarpey PS, Abidi F, Gecz J, Schwartz CE | display-authors = 6 | title = HUWE1 mutations in Juberg-Marsidi and Brooks syndromes: the results of an X-chromosome exome sequencing study | journal = BMJ Open | volume = 6 | issue = 4 | pages = e009537 | date = April 2016 | pmid = 27130160 | pmc = 4854010 | doi = 10.1136/bmjopen-2015-009537 }} Missense mutations in HUWE1 occur in multiple families with intellectual disability, including families with Juberg-Marsidi-Brooks syndrome.{{cite journal | vauthors = Isrie M, Kalscheuer VM, Holvoet M, Fieremans N, Van Esch H, Devriendt K | title = HUWE1 mutation explains phenotypic severity in a case of familial idiopathic intellectual disability | journal = European Journal of Medical Genetics | volume = 56 | issue = 7 | pages = 379–82 | date = July 2013 | pmid = 23721686 | doi = 10.1016/j.ejmg.2013.05.005 | hdl = 11858/00-001M-0000-0018-EE0C-9 | hdl-access = free }} Patients with missense mutations in HUWE1 share clinical features with patients with a duplication of HUWE1. This suggests both increased and decreased HUWE1 function could be associated with intellectual disability, but evidence from an in vivo model system supporting or refuting this possibility remains absent.

KDM5C (Lysine-Specific Demethylase 5C) also known as jumonji, A/T-rich interactive domain 1C (JARID1C) is located on the X chromosome at Xp11.22-p11.21. The gene encodes a 1560 amino-acid protein that belongs to the JARID1 subfamily of Arid DNA-binding proteins.{{cite journal | vauthors = Kortschak RD, Tucker PW, Saint R | title = ARID proteins come in from the desert | journal = Trends in Biochemical Sciences | volume = 25 | issue = 6 | pages = 294–9 | date = June 2000 | pmid = 10838570 | doi = 10.1016/S0968-0004(00)01597-8 }} The protein possesses H3K4me3-specific demethylase activity and is shown to function as a transcriptional repressor through the RE-1-silencing transcription factor (REST) complex.{{cite journal | vauthors = Iwase S, Lan F, Bayliss P, de la Torre-Ubieta L, Huarte M, Qi HH, Whetstine JR, Bonni A, Roberts TM, Shi Y | title = The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases | journal = Cell | volume = 128 | issue = 6 | pages = 1077–88 | date = March 2007 | pmid = 17320160 | doi = 10.1016/j.cell.2007.02.017 | doi-access = free }}

The mutations in KDM5C cause Claes-Jensen type{{cite journal | vauthors = Claes S, Devriendt K, Van Goethem G, Roelen L, Meireleire J, Raeymaekers P, Cassiman JJ, Fryns JP | title = Novel syndromic form of X-linked complicated spastic paraplegia | journal = American Journal of Medical Genetics | volume = 94 | issue = 1 | pages = 1–4 | date = September 2000 | pmid = 10982473 | doi = 10.1002/1096-8628(20000904)94:1<1::AID-AJMG1>3.0.CO;2-V }}{{cite journal | vauthors = Jensen LR, Amende M, Gurok U, Moser B, Gimmel V, Tzschach A, Janecke AR, Tariverdian G, Chelly J, Fryns JP, Van Esch H, Kleefstra T, Hamel B, Moraine C, Gecz J, Turner G, Reinhardt R, Kalscheuer VM, Ropers HH, Lenzner S | display-authors = 6 | title = Mutations in the JARID1C gene, which is involved in transcriptional regulation and chromatin remodeling, cause X-linked mental retardation | journal = American Journal of Human Genetics | volume = 76 | issue = 2 | pages = 227–36 | date = February 2005 | pmid = 15586325 | pmc = 1196368 | doi = 10.1086/427563 }} syndromic X-linked Intellectual Disability characterized by moderate-to-severe ID, speech abnormalities and other clinical findings such as seizures and aggressive behavior in some individuals.{{cite journal | vauthors = Rujirabanjerd S, Nelson J, Tarpey PS, Hackett A, Edkins S, Raymond FL, Schwartz CE, Turner G, Iwase S, Shi Y, Futreal PA, Stratton MR, Gecz J | title = Identification and characterization of two novel JARID1C mutations: suggestion of an emerging genotype-phenotype correlation | journal = European Journal of Human Genetics | volume = 18 | issue = 3 | pages = 330–5 | date = March 2010 | pmid = 19826449 | pmc = 2987212 | doi = 10.1038/ejhg.2009.175 }} There is also a report of a mutation in a patient with autism spectrum disorder.{{cite journal | vauthors = Adegbola A, Gao H, Sommer S, Browning M | title = A novel mutation in JARID1C/SMCX in a patient with autism spectrum disorder (ASD) | journal = American Journal of Medical Genetics. Part A | volume = 146A | issue = 4 | pages = 505–11 | date = February 2008 | pmid = 18203167 | doi = 10.1002/ajmg.a.32142 | s2cid = 31730709 }} A study showed that Kdm5c-knockout mice exhibit adaptive and cognitive abnormalities similar to those in human X-linked intellectual disability and concluded that histone methylation dynamics sculpt the neuronal network.{{cite journal | vauthors = Iwase S, Brookes E, Agarwal S, Badeaux AI, Ito H, Vallianatos CN, Tomassy GS, Kasza T, Lin G, Thompson A, Gu L, Kwan KY, Chen C, Sartor MA, Egan B, Xu J, Shi Y | title = A Mouse Model of X-linked Intellectual Disability Associated with Impaired Removal of Histone Methylation | journal = Cell Reports | volume = 14 | issue = 5 | pages = 1000–1009 | date = February 2016 | pmid = 26804915 | pmc = 4749408 | doi = 10.1016/j.celrep.2015.12.091 }}

IQ motif and Sec7 domain 2 (IQSEC2), also known as BRAG1 or IQ-ARFGEF, is located on the X chromosome at Xp11.22 and encodes guanine nucleotide exchange factor for the ARF family of GTP-binding proteins (ARFGEF).{{cite journal | vauthors = Nagase T, Ishikawa K, Suyama M, Kikuno R, Hirosawa M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O | title = Prediction of the coding sequences of unidentified human genes. XIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro | journal = DNA Research | volume = 6 | issue = 1 | pages = 63–70 | date = February 1999 | pmid = 10231032 | doi = 10.1093/dnares/6.1.63 | doi-access = free }} It is expressed in the neurons and is involved in cytoskeletal organization, dendritic spine morphology, and excitatory synaptic organization.{{cite journal | vauthors = Kalscheuer VM, James VM, Himelright ML, Long P, Oegema R, Jensen C, Bienek M, Hu H, Haas SA, Topf M, Hoogeboom AJ, Harvey K, Walikonis R, Harvey RJ | title = Novel Missense Mutation A789V in IQSEC2 Underlies X-Linked Intellectual Disability in the MRX78 Family | journal = Frontiers in Molecular Neuroscience | volume = 8 | pages = 85 | date = 2015 | pmid = 26793055 | pmc = 4707274 | doi = 10.3389/fnmol.2015.00085 | doi-access = free }}

Mutations in IQSEC2 are widely associated in cases of X-linked non-syndromic mental retardation, with some carrier females reported with learning disabilities.{{cite journal | vauthors = Shoubridge C, Tarpey PS, Abidi F, Ramsden SL, Rujirabanjerd S, Murphy JA, Boyle J, Shaw M, Gardner A, Proos A, Puusepp H, Raymond FL, Schwartz CE, Stevenson RE, Turner G, Field M, Walikonis RS, Harvey RJ, Hackett A, Futreal PA, Stratton MR, Gécz J | display-authors = 6 | title = Mutations in the guanine nucleotide exchange factor gene IQSEC2 cause nonsyndromic intellectual disability | journal = Nature Genetics | volume = 42 | issue = 6 | pages = 486–8 | date = June 2010 | pmid = 20473311 | pmc = 3632837 | doi = 10.1038/ng.588 }} This gene is known to play a significant role in the maintenance of homeostasis within the neural environment of the human brain. A change of guanine nucleotide exchange factor activity may influence the regulation of actin cytoskeleton organization and neuronal development in the brain by reduced activation of the ARF6 substrate or a defect in the GTP-binding activity.

Two intragenic duplications predicted to cause termination mutations on the X-chromosome involving IQSEC2 were identified in two de novo cases, and one nonsense mutation was described in three additional male patients presenting severe intellectual disability and additional clinical features including neonatal hypotonia, delayed motor skills, seizures, strabismus, autistic-like behavior, stereotypic midline hand movements, microcephaly, little-to-no walking, little-to-no language skills, significant behavioral issues, and mildly abnormal facial features.{{cite journal | vauthors = Tran Mau-Them F, Willems M, Albrecht B, Sanchez E, Puechberty J, Endele S, Schneider A, Ruiz Pallares N, Missirian C, Rivier F, Girard M, Holder M, Manouvrier S, Touitou I, Lefort G, Sarda P, Moncla A, Drunat S, Wieczorek D, Genevieve D | title = Expanding the phenotype of IQSEC2 mutations: truncating mutations in severe intellectual disability | journal = European Journal of Human Genetics | volume = 22 | issue = 2 | pages = 289–92 | date = February 2014 | pmid = 23674175 | pmc = 3895633 | doi = 10.1038/ejhg.2013.113 }} A novel de novo mutation in the IQSEC2 gene identified through diagnostic exome sequencing showed significant developmental delay, seizures, hypotonia, vision impairments, plagiocephaly, autistic-like features, absent language skills, and abnormal MRI findings.{{cite journal | vauthors = Gandomi SK, Farwell Gonzalez KD, Parra M, Shahmirzadi L, Mancuso J, Pichurin P, Temme R, Dugan S, Zeng W, Tang S | title = Diagnostic exome sequencing identifies two novel IQSEC2 mutations associated with X-linked intellectual disability with seizures: implications for genetic counseling and clinical diagnosis | journal = Journal of Genetic Counseling | volume = 23 | issue = 3 | pages = 289–98 | date = June 2014 | pmid = 24306141 | doi = 10.1007/s10897-013-9671-6 | s2cid = 17850707 | doi-access = free }} IQSEC2 gene plays a larger role in the cause of X-linked cognitive impairment than previously thought. Additional consideration is warranted with regards to the syndromic nature of its phenotypic association.

Testis-Specific Protein Y-encoded (TSPY) Like 2 (TSPYL2) codes for a member of the TSPY-like/SET/nucleosome assembly protein-1 superfamily and is located on the X chromosome at Xp11.22. The encoded protein is localized to the nucleolus where it functions in chromatin remodeling and as an inhibitor of cell-cycle progression.{{Cite web|url=https://www.ncbi.nlm.nih.gov/gene/64061|title=TSPYL2 TSPY like 2 [Homo sapiens (human)] - Gene - NCBI|website=www.ncbi.nlm.nih.gov|access-date=2018-03-01}} Consistent with a possible role for Tspyl2 pathways in neurodevelopment, Xp11.2 microduplication incorporating the TSPYL2 locus has been reported in male patients with Attention Deficit Hyperactivity Disorder.

Shroom Family Member 4 (SHROOM4), also known as KIAA1202, encodes a member of the APX/Shroom family, which contains an N-terminal PDZ domain and a C-terminal ASD2 motif. It is located on the X chromosome at Xp11.22 and is mainly associated with the Stocco dos Santos X-linked mental retardation syndrome characterized by cognitive disabilities.{{cite journal | vauthors = dos Santos RC, Barretto OC, Nonoyama K, Castro NH, Ferraz OP, Walter-Moura J, Vescio CC, Beçak W | title = X-linked syndrome: mental retardation, hip luxation, and G6PD variant [Gd(+) Butantan] | journal = American Journal of Medical Genetics | volume = 39 | issue = 2 | pages = 133–6 | date = May 1991 | pmid = 2063914 | doi = 10.1002/ajmg.1320390204 }} The encoded protein may play a role in cytoskeletal architecture. Symptoms of SHROOM4 gene mutations in the original family described by Stocco dos Santos include severe intellectual disability, bilateral congenital hip luxation and short stature. The SHROOM4 gene was also found to be disrupted in two unrelated females with mild to moderate intellectual disabilities. Other features included delayed or no speech, seizures, kyphosis and hyperactivity. Carrier females displayed seizures and depression. No mutations in SHROOM4 were identified in more than 1000 control X chromosomes.{{cite journal | vauthors = Stocco dos Santos RC, Castro NH, Lillia Holmes A, Beçak W, Tackels-Horne D, Lindsey CJ, Lubs HA, Stevenson RE, Schwartz CE | title = Stocco dos Santos X-linked mental retardation syndrome: clinical elucidation and localization to Xp11.3-Xq21.3 | journal = American Journal of Medical Genetics. Part A | volume = 118A | issue = 3 | pages = 255–9 | date = April 2003 | pmid = 12673656 | doi = 10.1002/ajmg.a.20021 | s2cid = 32244491 | doi-access = free }}

X-linked Intellectual Disability

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• [https://www.ncbi.nlm.nih.gov/projects/mapview/maps.cgi?TAXID=9606&CHR=X&MAPS=ideogr%2Ccntg-r%2CugHs%2Cgenes&BUILD=previous&BEG=48171793&END=52819683&oview=default NCBI Map Viewer]

Category:Rare genetic syndromes

Category:Genetic diseases and disorders