Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are major causes of blindness. They result from mutations in many genes which has long hampered comprehensive genetic analysis. Recently, targeted next-generation sequencing (NGS) has proven useful to overcome this limitation. To uncover “hidden mutations” such as copy number variations (CNVs) and mutations in non-coding regions, we extended the use of NGS data by quantitative readout for the exons of 55 RP and LCA genes in 126 patients, and by including non-coding 5′ exons. We detected several causative CNVs which were key to the diagnosis in hitherto unsolved constellations, e.g. hemizygous point mutations in consanguineous families, and CNVs complemented apparently monoallelic recessive alleles. Mutations of non-coding exon 1 of EYS revealed its contribution to disease. In view of the high carrier frequency for retinal disease gene mutations in the general population, we considered the overall variant load in each patient to assess if a mutation was causative or reflected accidental carriership in patients with mutations in several genes or with single recessive alleles. For example, truncating mutations in RP1, a gene implicated in both recessive and dominant RP, were causative in biallelic constellations, unrelated to disease when heterozygous on a biallelic mutation background of another gene, or even non-pathogenic if close to the C-terminus. Patients with mutations in several loci were common, but without evidence for di- or oligogenic inheritance. Although the number of targeted genes was low compared to previous studies, the mutation detection rate was highest (70%) which likely results from completeness and depth of coverage, and quantitative data analysis. CNV analysis should routinely be applied in targeted NGS, and mutations in non-coding exons give reason to systematically include 5′-UTRs in disease gene or exome panels. Consideration of all variants is indispensable because even truncating mutations may be misleading.
The purpose of our study was describing the meaning of pregnancy through Assisted Reproductive Technologies (ARTs). A qualitative design with hermeneutic phenomenology approach was selected to carry out the research. Semistructured in-depth interviews were conducted with 12 women who experienced assisted pregnancy. Three themes emerged from women's experience including finding peace in life, paradoxical feelings, and struggling to realize a dream. We concluded that pregnancy is the beginning of a new and hard struggle for women with fertility problems. The findings of our study resulted in helpful implications for the health care professionals managing assisted pregnancies.
Cryptic unbalanced chromosome rearrangements in the telomeric bands of human chromosomes constitute a significant cause of "idiopathic" mental retardation. Here, we have described a new strategy based upon comparative genomic hybridisation (CGH) to screen for these abnormalities.. A modified CGH analysis showed three unbalanced cryptic rearrangements in five patients from three families. These chromosome abnormalities and their balanced forms in the relatives were then confirmed by fluorescence in situ hybridisation (FISH). This study describes a new approach to the diagnosis of cryptic translocations between the G band negative ends of chromosomes and confirms the significant contribution ofcryptic telomeric rearrangements to idiopathic mental retardation. (aMed Get 1998;35:225-233)
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