First known microdeletion within the Wolf-Hirschhorn-syndrome critical region refines genotype-phenotype correlation

Deletions within HSA band 4p16.3 cause WoIf-Hirschhorn syndrome (WHS), whic h comprises mental retardation and developmental defects. A WHS critical re gion (WHSCR) of approximately 165 kb has been defined on the basis of 2 aty pical interstitial deletions; however, genotype-phenotype correlation remai ns controversial, due to the large size of deletion usually involving sever al megabases. We report on the first known patient with a small de novo int erstitial deletion restricted to the WHSCR who presented with a partial WHS phenotype consisting only of low body weight for height, speech delay, and minor facial anomalies; shortness of stature, microcephaly, seizures and m ental retardation were absent. The deletion was initially demonstrated by F ISH analysis, and breakpoints were narrowed with a "mini-FISH" technique us ing 3-5 kb amplicons. A breakpoint-spanning PCR assay defined the distal br eakpoint as disrupting the WHSC1 gene within intron 5, exactly after an Alu Jb repeat. The proximal breakpoint was not found to be associated with a re peated sequence or a known gene. The deletion encompasses 191.5 kb and incl udes WHSC2, but not LETM1. Thus, manifestations attributable to this deleti on are reduced weight for height, minor facial anomalies, ADHD and some lea rning and line motor deficiencies, while seizures may be associated with de letions of LETM1. (C) 2001 Wiley-Liss, Inc.