The chromosome 9q subtelomere deletion syndrome

Abstract

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.

Deep brain stimulation for the obsessive-compulsive and Tourette-like symptoms of Kleefstra syndrome

“…12,22,25 The behavioral and neuropsychiatric symptoms alleviated in our patient are common in Kleefstra syndrome but are frequently accompanied by other traits. Patients may demonstrate, with variable penetrance, autistic features, concentration and attention deficits, sleep disorders, anxiety, obsessive-compulsive symptoms, stereotypic movements and motor disorders, severe speech delay, lack of social interaction, and posturing.…”

“…25 Characterized by a phenotype of childhood hypotonia, intellectual disability, and distinctive facial features, this syndrome is often accompanied by myriad psychiatric and behavioral disorders. 12,22,25 While deep brain stimulation (DBS) has been used as a treatment for a number of neuropsychiatric conditions including obsessive-compulsive disorder (OCD), depression, and Tourette syndrome (TS), there is no literature on using DBS for the neuropsychiatric symptoms of a purely genetic disorder. In 1999, Nuttin and colleagues 18 were the first to describe the use of DBS for OCD, and their encouraging initial experience was confirmed with additional studies, 8,9,19 resulting in FDA approval of DBS for the treatment of OCD.…”

“…Patients may demonstrate, with variable penetrance, autistic features, concentration and attention deficits, sleep disorders, anxiety, obsessive-compulsive symptoms, stereotypic movements and motor disorders, severe speech delay, lack of social interaction, and posturing. 12,22,24 There is some evidence of a neurodegenerative, progressive apathy syndrome that becomes more evident in adolescence and adulthood. However, minimal literature documents the prevalence of such behavioral phenotypes.…”

A Modified Form of Diphthamide Causes Immunotoxin Resistance in a Lymphoma Cell Line with a Deletion of the WDR85 Gene

“…Defects in the EHMT1 gene are the cause of the chromosome 9q subtelomeric deletion syndrome. However, the 9q subtelomeric deletion syndrome is not known to increase susceptibility to cancer (32). Because the abnormal methylation of diphthamide occurs in cells with a deletion of EHMT1, it is unlikely that this protein has a role in the abnormal methylation we observed.…”

Trypanosoma brucei TIF2 suppresses VSG switching by maintaining subtelomere integrity

“…Drastically reduced D4Z4 repeat number can lead to abnormal DUX4 transcription and is associated with facioscapulohumeral muscular dystrophy (FSHD) [2]. Submicroscopic deletion of subtelomeric 6p25 and 9q has been recognized as clinically identifiable syndromes [3,4]. In addition, some OR genes encoding olfactory receptors are located at subtelomeres, and changes in subtelomeres contribute to the diversity of the OR gene family [5].…”