Abstract
In this paper we present the detailed clinical and cytogenetic analysis of a prenatally detected complex Congenital Diaphragmatic Hernia (CDH) patient with a mosaic unbalanced translocation (5;12). High-resolution whole genome SNP array confirmed a low-level mosaicism (20%) in uncultured cells, underlining the value of array technology for identification studies. Subsequently, targeted Fluorescence In-Situ Hybridization in postmortem collected tissues demonstrated a similar low-level mosaicism, independently of the affected status of the tissue. Thus, a higher incidence of the genetic aberration in affected organs as lung and diaphragm cannot explain the severe phenotype of this complex CDH patient. Comparison with other described chromosome 5p and 12p anomalies indicated that half of the features presented in our patient (including the diaphragm defect) could be attributed to both chromosomal areas. In contrast, a few features such as the palpebral downslant, the broad nasal bridge, the micrognathia, microcephaly, abnormal dermatoglyphics and IUGR better fitted the 5p associated syndromes only. This study underlines the fact that low-level mosaicism can be associated with severe birth defects including CDH. The contribution of mosaicism to human diseases and specifically to congenital anomalies and spontaneous abortions becomes more and more accepted, although its phenotypic consequences are poorly described phenomena leading to counseling issues. Therefore, thorough follow–up of mosaic aberrations such as presented here is indicated in order to provide genetic counselors a more evidence based prediction of fetal prognosis in the future.
Highlights
CDH and somatic mosaicism Congenital Diaphragmatic Hernia (CDH) is a severe birth defect characterized by defective formation of the diaphragm, lunghypoplasia and pulmonary hypertension
Cytogenetic analysis and MLPA A 22-year old Moroccan patient was referred to our tertiary centre for follow up and genetic counseling of a CDH detected in her unborn child by 20-weeks structural ultrasound in her first pregnancy
Based on these comparisons half of the features present in our patient could be attributed to both chromosomal areas. Exceptions to this were: the palpebral downslant, the broad-nasal bridge, the retro-and micro-gnathia, microcephaly, abnormal dermatoglyphics and IUGR, which better fit the 5p associated syndromes. In this case report we present the detailed clinical and cytogenetical analysis of a unique low-mosaic der (5) t(5;12) aberration identified in a CDH patient with multiple congenital anomalies
Summary
CDH and somatic (chromosomal) mosaicism Congenital Diaphragmatic Hernia (CDH) is a severe birth defect characterized by defective formation of the diaphragm, lunghypoplasia and pulmonary hypertension. Its overall prevalence is 1/3000 live births and the majority are left sided. Associated anomalies (i.e. non-isolated cases with or without an abnormal karyotype) are involved in 60% of cases. The mortality rate is still high: 10–20% for isolated and up to 40% for non-isolated cases. CDH is increasingly detected by structural ultrasound in the second trimester of pregnancy showing features like a mediastinal cardiac shift away from the side of the defect and an intra-thoracic stomach bubble [1]. Parents may opt for a termination of pregnancy and in case of continuation; obstetric and postnatal management can be optimized with referral to a specialized tertiary centre with ECMO (Extra Corporal Membrane Oxygenation) facilities
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