4p16.3 microdeletions and microduplications detected by chromosomal microarray analysis: New insights into mechanisms and critical regions

Abstract

Deletions in the 4p16.3 region cause Wolf–Hirschhorn syndrome, a well known contiguous microdeletion syndrome with the critical region for common phenotype mapped in WHSCR2. Recently, duplications in 4p16.3 were reported in three patients with developmental delay and dysmorphic features. Through chromosomal microarray analysis, we identified 156 patients with a deletion (n = 109) or duplication (n = 47) in 4p16.3 out of approximately 60,000 patients analyzed by Baylor Miraca Genetics Laboratories. Seventy‐five of the postnatally detected deletions encompassed the entire critical region, 32 (43%) of which were associated with other chromosome rearrangements, including six patients (8%) that had a duplication adjacent to the terminal deletion. Our data indicate that Wolf–Hirschhorn syndrome deletions with an adjacent duplication occur at a higher frequency than previously appreciated. Pure deletions (n = 14) or duplications (n = 15) without other copy number changes distal to or inside the WHSCR2 were identified for mapping of critical regions. Our data suggest that deletion of the segment from 0.6 to 0.9 Mb from the terminus of 4p causes a seizure phenotype and duplications of a region distal to the previously defined smallest region of overlap for 4p16.3 microduplication syndrome are associated with neurodevelopmental problems. We detected seven Wolf–Hirschhorn syndrome deletions and one 4p16.3 duplication prenatally; all of the seven are either >8 Mb in size and/or associated with large duplications. In conclusion, our study provides deeper insight into the molecular mechanisms, the critical regions and effective prenatal diagnosis for 4p16.3 deletions/ duplications. © 2016 Wiley Periodicals, Inc.

Wolf-Hirschhorn Syndrome: Clinical and Genetic Data from a First Case Diagnosed in Central Africa

“…14 The telomeric segment of 0.6 to 0.9 Mb is hypothesized to function synergistically with the seizure candidate region to promote seizures in WHS patients. 15 Our patient also presented the characteristic sacral dimples, located at the cranial part of the sacroiliac joints, a feature we find helpful in reaching this diagnosis.…”

IncreasedTBX6gene dosages induce congenital cervical vertebral malformations in humans and mice

“…To investigate the potential involvement of human 16p11.2 BP4-BP5 duplication in CVMs, we retrospectively reviewed the subjects with the 16p11.2 BP4-BP5 duplication from a large cohort of patients that were tested clinically by CMA due to various medical problems 46 47. The spinal X-ray images were available for seven 16p11.2 BP4-BP5 duplication carriers (figure 1A).…”

Cytogenomic Integrative Network Analysis of the Critical Region Associated with Wolf-Hirschhorn Syndrome

“…This region included seven candidate genes ( LETM1 , FGFR3 , WHSC1 , NELFA , C4orf48 , NAT8L , and POLN ). These genes could contribute to the pathogenic phenotype such as seizures and microcephaly and include the LETM1 gene located in our SRO, which contributes to the presence of seizures in a hemizygous deletion [ 1 , 12 , 18 , 30 ].…”

“…All patients in this study presented seizure symptoms, suggesting the putative involvement of this gene, although patients with 4p deletions, including LETM1 without seizures, or patients with seizures and the presence of LETM1 have been described [ 1 , 17 , 23 , 33 , 34 ]. However, this may be partially explained by the synergism between the phosphatidylinositol glycan anchor biosynthesis class G (PIGG) , complexin 1 (CPLX1) , and LETM1 genes, frequently associated with WHS convulsions [ 18 ].…”