A 1-Mb critical region in six patients with 9q34.3 terminal deletion syndrome

Harada, Naoki; Visser, Remco; Dawson, Angie; Fukamachi, Makoto; Iwakoshi, Mie; Okamoto, Nobuhiko; Kishino, Tatsuya; Niikawa, Norio; Matsumoto, Naomichi

doi:10.1007/s10038-004-0166-z

Cited by 36 publications

(22 citation statements)

References 17 publications

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“…Deletion sizing in approximately 25 published patients has ranged from 380 kb (Patient 3, Kleefstra et al, 2006a) to greater than 3 Mb (Patient A, Harada et al, 2004) and has relied relatively low-resolution methods (e.g., FISH probes, low-density SNP, and microsatellite genotyping). There are no published accounts of precise (base pair resolution) breakpoint mapping of chromosome 9q microdeletions in the 9qSTDS.…”

Section: Unanswered Questions/future Directions Genotype/phenotype Comentioning

confidence: 99%

The chromosome 9q subtelomere deletion syndrome

Stewart

Kleefstra²

2007

American J of Med Genetics Pt C

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The chromosome 9q subtelomere deletion syndrome (9qSTDS) is among the first and most common clinically recognizable syndromes to arise from widespread testing by fluorescent in situ hybridization (FISH) of subtelomere deletions. There are about 50 reported cases worldwide. Affected individuals invariably have severe hypotonia with speech and gross motor delay. The facial gestalt is distinct and features absolute or relative micro- or brachycephaly, hypertelorism, synophrys, and/or arched eyebrows, mid-face hypoplasia, a short nose with upturned nares, a protruding tongue with everted lower lip and down-turned corners of the mouth. Approximately half of affected individuals have congenital heart defects (primarily ASD or VSD). A significant minority have epilepsy and/or behavioral and sleep disturbances. A variety of other major and minor eye, ear, genital, and limb anomalies have been reported. Most patients have sub-microscopic deletions of the subtelomere region of chromosome 9q34.3 that range from <400 kb to >3 Mb. The 9qSTDS is caused by haplo-insufficiency of EHMT1, a gene whose protein product (Eu-HMTase1) is a histone H3 Lys 9 (H3-K9) methyltransferase. This was established by identification of three patients with features of the syndrome and either mutations or a balanced translocation in EHMT1. H3-K9 histone methylation is restricted to the euchromatin of mammals and functions to silence individual genes. Deletion size does not correlate with the severity of the 9qSTDS since patients with mutations in EHMT1 are as severely affected as those with submicroscopic deletions. Patients clinically suspected of having the 9qSTDS but with normal subtelomere deletion testing by FISH or MLPA should be considered for detailed 9q MLPA analysis and/or sequencing of EHMT1. EHMT1 is another example in the growing list of genes responsible for brain development that appear to play a role in chromatin remodeling. Published 2007 Wiley-Liss, Inc.

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Section: Unanswered Questions/future Directions Genotype/phenotype Comentioning

confidence: 99%

The chromosome 9q subtelomere deletion syndrome

Stewart

Kleefstra²

2007

American J of Med Genetics Pt C

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“…The syndrome is either caused by a submicroscopic deletion in the chromosomal region 9q34.3 or an intragenic mutation of the euchromatin histone methyltransferase 1 (EHMT1) gene causing haploinsufficiency of EHMT1 . So far, 85 patients, including 75 patients with a 9q34.3 deletion and 10 patients with an EHMT1 mutation, have been reported [Schimmenti et al, 1994;Ayyash et al, 1997;Dawson et al, 2002;Cormier-Daire et al, 2003;Font-Montgomery et al, 2004;Harada et al, 2004;Iwakoshi et al, 2004;Stewart et al, 2004;Neas et al, 2005;Yatsenko et al, 2005Yatsenko et al, , 2009Kleefstra et al, 2006aKleefstra et al, , b, 2009Stewart and Kleefstra, 2007;Verhoeven et al, 2010;Willemsen et al, 2011]. EHMT1 encodes a histone H3 Lys 9 methyltransferase and is thereby involved in chromatin remodeling [Ogawa et al, 2002].…”

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confidence: 99%

Update on Kleefstra Syndrome

et al. 2011

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Kleefstra syndrome is characterized by the core phenotype of developmental delay/intellectual disability, (childhood) hypotonia and distinct facial features. The syndrome can be either caused by a microdeletion in chromosomal region 9q34.3 or by a mutation in the euchromatin histone methyltransferase 1 (EHMT1) gene. Since the early 1990s, 85 patients have been described, of which the majority had a 9q34.3 microdeletion (>85%). So far, no clear genotype-phenotype correlation could be observed by studying the clinical and molecular features of both 9q34.3 microdeletion patients and patients with an intragenic EHMT1 mutation. Thus, to further expand the genotypic and phenotypic knowledge about the syndrome, we here report 29 newly diagnosed patients, including 16 patients with a 9q34.3 microdeletion and 13 patients with an EHMT1 mutation, and review previous literature. The present findings are comparable to previous reports. In addition to our former findings and recommendations, we suggest cardiac screening during follow-up, because of the possible occurrence of cardiac arrhythmias. In addition, clinicians and caretakers should be aware of the regressive behavioral phenotype that might develop at adolescent/adult age and seems to have no clear neurological substrate, but is rather a so far unexplained neuropsychiatric feature.

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“…qter deletion or duplication without the involvement of another chromosome. Harada et al [1989] has described a case with similar de novo unbalanced translocation with comparable breakpoints, and recent molecular delineation of the breakpoint in the same patient by Harada et al [2004] showed that the deletion is larger than the shortest 1Mb deletion region overlap in other patients investigated in their recent studies. As seen from the CGH microarray studies, our patient also demonstrated a deletion exceeding this smallest deleted region (Fig.…”

Section: Discussionmentioning

confidence: 94%

“…Utilization of FISH techniques and CGH microarray technology in our family determined that the two subtelomeric probes were missing in the proband with retention of the ABL and ASS loci at 9q34.1. Additionally, based on the CGH microarray analysis, the deletion in our patient is larger than the smallest critical region of 1 Mb region determined by Harada et al [2004] as well as the 1.2Mb minimum commonly deleted region observed in the patients investigated by Stewart et al [2004].…”

Section: Discussionmentioning

confidence: 96%

Cryptic duplication and deletion of 9q34.3 → qter in a family with a t(9;22)(q34.3;p11.2)

et al. 2005

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A newborn male was referred for genetic evaluation because of multiple congenital abnormalities. Physical findings included a round face, telecanthus, hypertelorism, a short upturned nose with anteverted nares, small ears, micrognathia, short toes, and congenital heart disease. Chromosome analysis detected a possible deletion of 9qter because of satellite material on 9qter. Delineation by FISH and microarray CGH studies showed 46,XY,der(9)t(9;22)(q34.3;p11.2). The mother and maternal grandfather had a balanced t(9;22)(q34.3;p11.2) rearrangement. Also, the maternal great-aunt of the propositus was found to have a duplication of 9q34.3 --> qter. FISH was required to delineate her karyotype, which was 46,XX.ish der(22)t(9;22)(q34.3;p11.2). This maternal great-aunt and one of her daughters (cytogenetics not done) have a relatively normal phenotype, only reporting mild learning disabilities in school. Since the 22p material involved in this rearrangement is clinically irrelevant, this report describes an individual with a pure deletion of 9q34.3 --> qter and another with a pure duplication of 9q34.3 --> qter.

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A 1-Mb critical region in six patients with 9q34.3 terminal deletion syndrome

Cited by 36 publications

References 17 publications

The chromosome 9q subtelomere deletion syndrome

The chromosome 9q subtelomere deletion syndrome

Update on Kleefstra Syndrome

Cryptic duplication and deletion of 9q34.3 → qter in a family with a t(9;22)(q34.3;p11.2)

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