European Journal of Human Genetics最新文献

X-linked retinitis pigmentosa (XLRP) is characterized by progressive vision loss leading to legal blindness in males and a broad severity spectrum in carrier females. Pathogenic alterations of the retinitis pigmentosa GTPase regulator gene (RPGR) are responsible for over 70% of XLRP cases. In the retina, the RPGR^ORF15 transcript includes a terminal exon, called ORF15, that is altered in the large majority of RPGR-XLRP cases. Unfortunately, due to its highly repetitive sequence, ORF15 represents a considerable challenge in terms of sequencing for molecular diagnostic laboratories. However, in a recent preliminary work Yahya et al. reported a long-read sequencing approach seeming promising. Here, the aim of the study was to validate and integrate this new sequencing strategy in a routine screening workflow. For that purpose, we performed a masked test on 52 genomic DNA samples from male and female individuals carrying 32 different pathogenic ORF15 variations including 20 located in the highly repetitive region of the exon. For the latter, we have obtained a detection rate of 80-85% in males and 60-80% in females after bioinformatic analyses. These numbers raised to 100% for both status after adding a complementary visual inspection of ORF15 long-reads. In accordance with these results, and considering the frequency of ORF15 pathogenic variations in XLRP, we suggest that a long-read screening of ORF15 should be systematically considered before any other sequencing approach in subjects with a diagnosis compatible with XLRP.

This article explores the significance of lived experience to understandings of severity in the genomic age. It draws upon data from structured interviews with 21 people living with monogenic conditions in England. The article argues that while lived experiences are subjective, participants consider the severity of disease by the impact a condition has on a person's quality of life and mental health; both of these interplays are influenced by social, economic, and environmental factors. The three factors and considerations to the impact of living with disease on mental health are generally absent from current frameworks designed to assess severity for clinical applications of genomic technologies such as preimplantation genetic testing (PGT). This article describes ways in which such factors impact the quality of life and the mental health of people living with genetic conditions. It also indicates what lived experiences, which illustrate the impact of these factors, have to offer policy-makers when they are assessing the concept of severity or seriousness of genetic conditions for applications of existing and potential genomic technologies in the genomic age.

Osteogenesis Imperfecta (OI) is a clinically and genetically heterogeneous group of diseases characterized by brittle bones. Though genetic mutations in COL1A1 and COL1A2 account for approximately 85-90% of OI cases, there are now more than twenty genes described, responsible for rare forms of OI. Treatment is based on the use of bisphosphonates and though it is well established that they increase lumbar spine (LS) bone mineral density (BMD), the clinical impact on fracture reduction is still debated.In this study, we investigated the clinical characteristics of 38 patients with a bone fragility disorder that had variants in non-COL1A1/COL1A2 genes in order to study genotype-phenotype correlations, as the natural history of these rare forms is still not well known. We then studied the usefulness of bisphosphonate treatment by evaluating the effects on LS BMD, annual non-vertebral fracture rate, bone turnover markers and height. This study enabled us to better define the natural history of patients with non-COL1 pathogenic variants. Patients with CRTAP and TMEM38B variants consistently had a prenatal presentation with a short (<3^rd p) and bowed femur. Importantly, this prenatal involvement does not predict the postnatal severity of the disease. Regarding treatment by bisphosphonates, all patients showed a significant increase in LS BMD while treated and this increase was dependent on the dose received. The increase in LS BMD also translated in a reduction of fracture rate during treatment. Finally, our study showed that the earlier bisphosphonates are initiated, the greater the fracture rate is reduced.

Haploinsufficiency of the short stature homeobox-containing (SHOX) gene leads to a phenotypic spectrum ranging from Leri-Weill dyschondrosteosis (LWD) to SHOX-deficient short stature. SHOX nullizygosity leads to Langer mesomelic dysplasia. Pathogenic variants can include whole or partial gene deletions or duplications, point mutations within the coding sequence, and deletions of upstream and downstream regulatory elements. Here we report two families: a non-consanguineous family with a deletion downstream of SHOX, in which the homozygous proband presented with isolated Madelung deformity, without LWD or short stature, as well as a 9-year-old girl with Madelung deformities, mesomelia, a dominant family history of Madelung deformity and a heterozygous deletion of the CNE9 region in the 3' downstream region of SHOX. These case reports provide additional information on the effects of 3' downstream deletions of SHOX, by demonstrating the limited phenotype associated with the recurrent 47.5 kb deletion in a homozygous state and the CNE9 deletion in a heterozygous state.