Calibration of 6q subtelomere deletions to define genotype/phenotype correlations

Abstract

Testing for subtelomere abnormalities in patients with idiopathic mental retardation has become a useful diagnostic tool. However, limited data exist regarding genotype/phenotype correlations for specific subtelomere imbalances. We have ascertained five patients with 6q subtelomere deletions either as a result of an isolated deletion or as a result of an unbalanced translocation, and developed a molecular ruler assay utilizing BAC or PAC clones and determined the size of the deleted regions to range from <0.5 to 8 Mb. To establish genotype/phenotype correlations for distal 6q, we compared the clinical features of these patients to previously reported cases of 6q subtelomere and cytogenetically visible deletions and found that they shared multiple abnormalities, suggesting that the causative genes may lie in the region of the smallest 6q subtelomeric deletion, approximately 400 kb from the telomere. However, multiple unique features were present only in patients with cytogenetically visible 6q deletions, indicative that genes involved in the development of these features may lie more proximally on 6q. These initial studies demonstrate the ability to develop genotype/phenotype correlations for subtelomere rearrangements, which will aid in the diagnosis and prognosis of these patients and may help narrow the search for relevant developmental genes.

Delineation of candidate genes responsible for structural brain abnormalities in patients with terminal deletions of chromosome 6q27

“…[1][2][3][4][5][6][7][8][9]15,16 Though the clinical phenotypes associated with this deletion are quite variable, reports in unrelated subjects from independent investigators have shown that ACC, PNH, polymicrogyria, hydrocephalus, and cerebellar malformations are the consistently observed features. A recent analysis of a comprehensive map of loci for ACC from 374 patients revealed that chromosome 6q27 was one of the few loci wherein six or more subjects with ACC have been reported.…”

“…Structural brain malformations are consistently observed in these patients and include agenesis of the corpus callosum (ACC), periventricular nodular heterotopia (PNH), polymicrogyria, hydrocephalus, and cerebellar malformations. [1][2][3][4][5][6][7][8][9][10] Whereas previous studies have attempted to delineate the critical region responsible for brain malformations in patients with terminal 6q27 deletions, the sensitivity of the methodologies used has prevented the fine-mapping of the critical region. 1,6 A detailed genomic analysis of the subtelomeric chromosome 6q region would help identify the putative genes involved in the causation of brain malformations.…”

“…1 This region contains only three protein-coding genes, PSMB1, TBP, and PDCD2, encoding a proteasome subunit, a TATA box binding protein, and a nuclear protein involved in programmed cell death, respectively, and exhibit significant conserved synteny. 31,32 TBP encodes for TATA-binding protein that associates with TBP-associated factors to form transcription factor IID that is critical for initiation of transcription.…”

Comprehensive validation of array comparative genomic hybridization platforms: how much is enough?

“…This presents a significant diagnostic problem because patients with 6qter deletions smaller than 1.7 Mb have a clinical phenotype. 16 Finally, abnormalities involving mismapped or poorly performing clones that are proximal to the most terminal clones could be misinterpreted as noncontiguous deletions or duplications. For example, the third and fourth clones from the 7q subtelomere (RP11-324E12 and RP11-11B21, Table 2) are both mismapped, leading to confusing and potentially misleading results.…”

Hypomorphic Pathogenic Variants in TAF13 Are Associated with Autosomal-Recessive Intellectual Disability and Microcephaly

“…Variants in TAF1 are associated with ID and microcephaly 13,14 whereas the reduction in TAF1 expression is associated with XDP 10 (Table S1). Also, in TBP, the expansion of the polyglutamine (polyQ) tract causes SCA17 probably in a gain-of-function mode, whereas heterozygous deletion of TBP is probably responsible for ID and microcephaly 9,29 (Table S1). Therefore, we also suggest that TAF13 and possibly other constituents of TFIID are multi-functional proteins whose pathogenic variants could lead to different phenotypes depending on the localization of the pathogenic variant.…”