Comprehensive analysis of Wolf–Hirschhorn syndrome using array CGH indicates a high prevalence of translocations

Abstract

Wolf-Hirschhorn syndrome (WHS) is caused by deletions involving chromosome region 4p16.3. The minimal diagnostic criteria include mild-to-severe mental retardation, hypotonia, growth delay and a distinctive facial appearance. Variable manifestations include feeding difficulties, seizures and major congenital anomalies. Clinical variation may be explained by variation in the size of the deletion. However, in addition to having a deletion involving 4p16.3, previous studies indicate that approximately 15% of WHS patients are also duplicated for another chromosome region due to an unbalanced translocation. It is likely that the prevalence of unbalanced translocations resulting in WHS is underestimated since they can be missed using conventional chromosome analyses such as karyotyping and WHS-specific fluorescence in situ hybridization (FISH). Therefore, we hypothesized that some of the clinical variation may be due to an unrecognized and unbalanced translocation. Array comparative genomic hybridization (aCGH) is a new technology that can analyze the entire genome at a significantly higher resolution over conventional cytogenetics to characterize unbalanced rearrangements. We used aCGH to analyze 33 patients with WHS and found a much higher than expected frequency of unbalanced translocations (15/33, 45%). Seven of these 15 cases were cryptic translocations not detected by a previous karyotype combined with WHS-specific FISH. Three of these 15 cases had an unbalanced translocation involving the short arm of an acrocentric chromosome and were not detected by either aCGH or subtelomere FISH. Analysis of clinical manifestations of each patient also revealed that patients with an unbalanced translocation often presented with exceptions to some expected phenotypes.

Wolf-Hirschhorn Syndrome (WHS), A Case Report and Review of Literature Submit Manuscript

“…About half of the patients with WHS have a de novo simple deletion of 4p16.3, while 40-45% of patients with WHS have an unbalanced translocation with both a deletion of 4p and a partial trisomy of a different chromosome arm [18]. South et al [19] conducted two studies, which demonstrated that the rates of unbalanced translocations involving 4p in WHS is certainly higher than reported previously and is approximately 45% [19].…”

Fine-grained facial phenotype–genotype analysis in Wolf–Hirschhorn syndrome

“…7 Translocations between chromosomes 4 and 8 occur more frequently than expected. [7][8][9][10][11] WHS is characterized by pre-and postnatal growth delay, microcephaly, seizures, hypotonia, developmental delay, congenital anomalies and a recognizable facial appearance, which includes: hypertelorism, protruding eyes, epicanthus, arched eyebrows, prominent nasal bridge, downturned corners of the mouth, micrognathia and short philtrum, and, with increasing age, a more prominent nose. Dental anomalies, some occurring in more than half of WHS patients, have been described: delayed eruption and hypodontia, retained primary teeth, peg-shaped teeth and taurodontism.…”

Deletions involving genes WHSC1 and LETM1 may be necessary, but are not sufficient to cause Wolf–Hirschhorn Syndrome

“…WHS is most often caused by terminal deletions, however, interstitial deletions, unbalanced translocations and complex genomic rearrangements account for a significant proportion of cases. 2,5 The majority of 4p deletions are non-recurrent. Genotype-phenotype correlation studies have shown a relationship between deletion size and severity of clinical presentation.…”

“…8,11 Beyond this region, the loss of additional critical genes appears to be responsible for variably present features, such as congenital malformations or hearing loss. 1,5,8 The identification of patients with atypical 4p deletions has provided key insight into which regions of 4p16.3 may (or may not) contribute to the pathogenesis of WHS. For example, small terminal deletions (up to 400 kb) have been inherited from phenotypically normal individuals; [12][13][14] indicating that monosomy of this region is likely benign.…”