Diagnosis of Familial Wolf-Hirschhorn Syndrome due to a Paternal Cryptic Chromosomal Rearrangement by Conventional and Molecular Cytogenetic Techniques

Abstract

The use of conventional cytogenetic techniques in combination with fluorescent in situ hybridization (FISH) and single-nucleotide polymorphism (SNP) microarrays is necessary for the identification of cryptic rearrangements in the diagnosis of chromosomal syndromes. We report two siblings, a boy of 9 years and 9 months of age and his 7-years- and 5-month-old sister, with the classic Wolf-Hirschhorn syndrome (WHS) phenotype. Using high-resolution GTG- and NOR-banding karyotypes, as well as FISH analysis, we characterized a pure 4p deletion in both sibs and a balanced rearrangement in their father, consisting in an insertion of 4p material within a nucleolar organizing region of chromosome 15. Copy number variant (CNV) analysis using SNP arrays showed that both siblings have a similar size of 4p deletion (~6.5 Mb). Our results strongly support the need for conventional cytogenetic and FISH analysis, as well as high-density microarray mapping for the optimal characterization of the genetic imbalance in patients with WHS; parents must always be studied for recognizing cryptic balanced chromosomal rearrangements for an adequate genetic counseling.

Wolf-Hirschhorn Syndrome: Clinical and Genetic Study of 7 New Cases, and Mini Review

“…This was not surprising because approximately 15% of cases with WHS are generated by a mis-segregation of derivative chromosomes in meiosis of a carrier of balanced translocation [ 14 ]. The most common translocations in WHS are with the chromosome 8p, followed closely by translocations with 7p, 11p, 12p [ 15 ]. Patients with an unbalanced translocation usually present some deviation from classic clinical manifestations due to modification of the phenotype by the trisomy material [ 14 ].…”

“…We can presume in this case that a mechanism characterized by a telomere-to-telomere fusion which generates a pseudo-complete ring chromosome, associated with a small loss of genetic material is responsible for microdeletion in terminal part of short arm of chromosome 4. However, such cases are very rare and represent not more than >1% of WHS [ 15 , 16 ].…”