Clinical and genomic characterization of distal duplications and deletions of chromosome 4q: study of two cases and review of the literature

Abstract

Variable clinical presentations of patients with chromosomally detected deletions in the distal long arm (q) of chromosome 4 have been reported. The lack of molecular characterization of the deletion sizes and deleted genes hinders further genotype-phenotype correlation. Using a validated oligonucleotide array comparative genomic hybridization (oaCGH) analysis, we examined two patients with apparent chromosomal deletions in the distal 4q region. In the first, oaCGH identified a 2.441 megabase (Mb) duplication and a 12.651 Mb deletion at 4q34.1 in a pregnant female who transmitted this aberration to her son. This mother has only learning disabilities while her son had both renal and cardiac anomalies in the newborn period. Unrecognized paternal genetic factors may contribute to the variable expression. The second patient is a 17-year-old female with a history of Pierre Robin sequence, cardiac abnormalities and learning disabilities. She was diagnosed prenatally with a de novo 4q deletion, and oaCGH defined a 16.435 Mb deletion of 4q34.1-4q35.2. Phenotypic comparison and subtractive genomic mapping between these two cases suggested a 4 Mb region possibly harboring a candidate gene for Pierre Robin sequence. Our cases and review of reported cases with genomic findings indicated the presence of familial variants with variable expressivity as well as de novo or inherited pathogenic simple deletion, duplication and complex deletion and duplication in the distal 4q region.

Fig. 1

A: Pedigree of the three-generation family with 4q distal duplication and deletion, fill box indicates affected subjects and arrow to the proband. B: Left panel shows chromosomes 4 of the proband (II-2) and her son (III-1). The deletion was designated to the distal portion of 4q34.3 and the duplication of 4q34.1q34.3 was not evident at a resolution of 550 bands. Right panel shows metaphase-FISH confirming the del(4q) in the proband using subtelomeric 4pter (green), 4qter (red) and 21qter (yellow) probes. C: Chromosome 4 oaCGH data for the parents (II-1 and II-2) and their child (III-1). The proband and her child carry an identical duplication/deletion of chromosome 4. Base pair designations of the copy number gain (chr4;175,649,768–178,091,166) and copy number loss (chr4:178,470,008–191,121,285) are according to the March 2006 (hg18) human reference sequence (http://genome.ucsc.edu/).

Fig. 2

Front and side view of the patient from case 2 at 8 years old.

Fig. 3

The oaCGH analysis on Case 2 shows loss of one copy of the distal portion of chromosome 4 (chr4:174,685,919–191,121,195). A 4q deletion, del(4)(q34.1), is shown in the inset.

Fig. 4

Genomic findings of pathogenic deletions, duplications and complex rearrangements in the distal 4qter region. Critical regions associated with DD/MR/MCA and PRS/DA/CHD and possible candidate genes were shown. (DD: developmental delay, MR: mental retardation, MCA: multiple congenital anomalies, PRS: Pierre Robin sequence, DA: digital anomalies, CHD: congenital heart defects, number within parenthesis denoted number of cases in the report).