Delineation of two distinct 6p deletion syndromes

Abstract

Deletions of the short arm of chromosome 6 are relatively rare, the main features being developmental delay, craniofacial malformations, hypotonia, and defects of the heart and kidney, with hydrocephalus and eye abnormalities occurring in some instances. We present the molecular cytogenetic investigation of six cases with 6p deletions and two cases with unbalanced translocations resulting in monosomy of the distal part of 6p. The breakpoints of the deletions have been determined accurately by using 55 well-mapped probes and fluorescence in situ hybridization (FISH). The cases can be grouped into two distinct categories: interstitial deletions within the 6p22-p24 segment and terminal deletions within the 6p24-pter segment. Characteristics correlating with specific regions are: short neck, clinodactyly or syndactyly, brain, heart and kidney defects with deletions within 6p23-p24; and corneal opacities/iris coloboma/Rieger anomaly, hypertelorism and deafness with deletions of 6p25. The two cases with unbalanced translocations presented with a Larsen-like syndrome including some characteristics of the 6p deletion syndrome, which can be explained by the deletion of 6p25. Such investigation of cytogenetic abnormalities of 6p using FISH techniques and a defined set of probes will allow a direct comparison of reported cases and enable more accurate diagnosis as well as prognosis in patients with 6p deletions.

Cryptic subtelomeric 6p deletion in a girl with congenital malformations and severe language impairment

“…13 In addition, chromosome aberrations including 6p25 have been reported together with anterior segment malformations and additional clinical findings. 1,3,14 The FOX-gene FOXC1 is located in the critical IRID1 region and deleted in our patient, and mutations in this gene have been found in familial and isolated cases with anterior chamber anomalies. However, not all families with anterior chamber defects mapped to 6p25 have mutations in the FOXC1 gene, which implies the presence of other genes involved in eye development in the region.…”

“…Knight et al reported a case with a 6p deletion estimated to 6.4 -8.6 cM, but did not include clinical data beside mental retardation. 4 Davies et al 3 compared the clin- Figure 1 Facial appearance of the patient at age 4 years and 9 months.…”

“…The deletions can be grouped into two separate categories: terminal deletions with breakpoints within the 6p24-pter region, and interstitial deletions with breakpoints within the 6p22-p24 region. 3 The terminal deletions do not seem to overlap with the region of the interstitial deletions, and the clinical phenotypes differ significantly. Short neck, hand abnormalities, structural eye abnormalities, brain, kidney and heart defects are commonly associated with the interstitial deletions, and defects of the anterior eye-chamber development, hearing loss, heart malformations, hypertelorism, mid-face hypoplasia and low set ears are found among the terminal deletions.…”

Ablation of cyclase-associated protein 2 (CAP2) leads to cardiomyopathy

“…The human CAP2 gene is present on chromosome 6, specifically at 6p22.3. Davies et al [34] reported a new interstitial 6p22-24 deletion syndrome after finding several cases with this type of deletion. The patients studied showed various cardiac defects along with other developmental abnormalities.…”

Axenfeld–Rieger syndrome and spectrum of PITX2 and FOXC1 mutations

“…56 Such long-range position effects have previously been suggested for other disorders 57 and interestingly FOXC1 has also been associated with long-range position effects. 58 Some of the missense mutations leading to amino acid substitutions and other types of mutations have been investigated by functional studies and these mutations alter the protein function in varying degrees (Tables 2 -3 and Supplementary Figures 1 -2). Most of the intragenic PITX2 mutations are loss-of-function mutations, which result in defective DNA binding, decreased transactivation capability of downstream genes, or both (Table 2).…”