European Archives of Oto-Rhino-Laryngology / Whole-exome sequencing to identify the cause of congenital sensorineural hearing loss in carriers of a heterozygous GJB2 mutation

Bi-allelic variations in the gap junction protein beta-2 (GJB2) gene cause up to 50% of cases of newborn hearing loss. Heterozygous pathogenic GJB2 variations are also fivefold overrepresented in idiopathic patient groups compared to the normal-hearing population. Whether hearing loss in this group is due to unidentified additional variations within GJB2 or variations in other deafness genes is unknown in most cases. Whole-exome sequencing offers an effective approach in the search for causative variations in patients with Mendelian diseases. In this prospective genetic cohort study, we initially investigated a family of Turkish origin suffering from congenital autosomal recessive hearing loss. An index patient and his normal-hearing father, both bearing a single heterozygous pathogenic c.262G>T (p.Ala88Ser) GJB2 transversion as well as the normal-hearing mother were investigated by means of whole-exome sequencing. Subsequently the genetic screening was extended to a hearing-impaired cohort of 24 families of Turkish origin. A homozygous missense c.5492G>T transversion (p.Gly1831Val) in the Myosin 15a gene, previously linked to deafness, was identified as causative in the index family. This very rare variant is not listed in any population in the Genome Aggregation Database. Subsequent screening of index patients from additional families of Turkish origin with recessive hearing loss identified the c.5492G>T variation in an additional family. Whole-exome sequencing may effectively identify the causes of idiopathic hearing loss in patients bearing heterozygous GJB2 variations.(VLID)355285

Wiener klinische Wochenschrift / Identification of a rare COCH mutation by whole-exome sequencing : Implications for personalized therapeutic rehabilitation in an Austrian family with non-syndromic autosomal dominant late-onset hearing loss

Background Non-syndromic autosomal dominant hearing impairment is characteristically postlingual in onset. Genetic diagnostics are essential for genetic counselling, disease prognosis and understanding of the molecular mechanisms of disease. To date, 36 causative genes have been identified, many in only individual families. Gene selection for genetic screening by traditional methods and genetic diagnosis in autosomal dominant patients has therefore been fraught with difficulty. Whole-exome sequencing provides a powerful tool to analyze all protein-coding genomic regions in parallel, thus allowing the comprehensive screening of all known genes and associated alterations. Methods In this study, a previously undiagnosed late-onset progressive autosomal dominant hearing loss in an Austrian family was investigated by means of whole-exome sequencing. Results were confirmed by Sanger sequencing. Results A previously described c.151C>T missense (p.Pro51Ser) mutation in the LCCL (limulus factor C, cochlin, late gestation lung protein Lgl1) domain of the cochlin gene (COCH) was identified as causative and segregated with disease in five members of the family. Molecular diagnostics led to the decision to perform cochlear implantation in an index patient who subsequently showed excellent postoperative auditory performance. The c.151C>T mutation was not found in 18 screened Austrian families with autosomal dominant hearing loss but was represented alongside other known pathogenic mutant COCH alleles in the Genome Aggregation Database (gnomAD) in European populations. A combined allele frequency of 0.000128 implies an orphan disease frequency for COCH-induced hearing loss of 1:3900 in Europe. Conclusions Exome sequencing successfully resolved the genetic diagnosis in a family suffering from autosomal dominant hearing impairment and allowed prediction of purported auditory outcome after cochlear implantation in an index patient. Personalized treatment approaches based on the molecular mechanisms of disease may become increasingly important in the future.(VLID)358224

A homozygous deletion of a normal variation locus in a patient with hearing loss from non-consanguineous parents

International audienceInternational databases with information on copy number variation of the human genome are an important reference for laboratories using high resolution whole genome screening. Genomic deletions or duplications which have been detected in the healthy population and thus marked as normal copy number variants (CNVs) can be filtered out using these databases when searching for pathogenic copy number changes in patients. However, a potential pitfall of this strategy is that reported normal CNVs often do not elicit further investigation, and thus may remain unrecognized when they are present in a (pathogenic) homozygous state. The impact on disease of CNVs in the homozygous state may thus remain undetected and underestimated

A randomized trial comparing renal function in older kidney transplant patients following delayed versus immediate tacrolimus administration

BACKGROUND: This large, randomized, multicenter trial evaluated if basiliximab induction and delayed tacrolimus can preserve renal function in older kidney transplant patients. METHODS: Patients aged 60 years and older received delayed tacrolimus with basiliximab and mycophenolate mofetil with early steroid discontinuation (Tac-d, n=132) or standard tacrolimus with mycophenolate mofetil and steroids until day 91 (Tac-s, n=122). Tacrolimus trough levels were 5 to 10 ng/mL after day 43 in both groups. Renal function at month 6 was measured by calculated creatinine clearance (Cockcroft-Gault formula). RESULTS: In both groups, mean recipient age was 66 years, mean donor age was 63 years with 73% of donors aged 60 years and older. Steroid discontinuation was slower than protocol specified. In the Tac-d group, 56.1% were steroid free at day 14 and 81.8% at month 6. In the Tac-s group, 37.7% were steroid free at month 4 and 63.9% at month 6. Mean (+/-SD) calculated creatinine clearance was 45.7+/-16.1 mL/min (Tac-d) and 45.0+/-18.2 mL/min (Tac-s) (P=ns), mean glomerular filtration rate (modified diet in renal disease formula) was 44.9+/-16.2 mL/min and 41.6+/-16.8 mL/min, respectively. Incidences of biopsy-proven acute rejection were 18.9% (Tac-d) and 18.0% (Tac-s). Delayed graft function was 30.3% (Tac-d) and 23.8% (Tac-s). Estimated patient survival rates (Kaplan-Meier) in the Tac-d and Tac-s groups were 96.1% vs. 99.2% and estimated graft survival rates were 90% vs. 87.6%, respectively. Safety results were similar with both regimens. CONCLUSION: Delayed tacrolimus with basiliximab induction did not provide an advantage in preserving renal function or reducing delayed graft function in older kidney transplant patients