A Known Pathogenic Variant in the Essential Mitochondrial Translation Gene RMND1 Causes a Perrault-Like Syndrome with Renal Defects

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Recent developments in genetics and medically assisted reproduction : from research to clinical applications

Two leading European professional societies, the European Society of Human Genetics and the European Society for Human Reproduction and Embryology, have worked together since 2004 to evaluate the impact of fast research advances at the interface of assisted reproduction and genetics, including their application into clinical practice. In September 2016, the expert panel met for the third time. The topics discussed highlighted important issues covering the impacts of expanded carrier screening, direct-to-consumer genetic testing, voiding of the presumed anonymity of gamete donors by advanced genetic testing, advances in the research of genetic causes underlying male and female infertility, utilisation of massively parallel sequencing in preimplantation genetic testing and non-invasive prenatal screening, mitochondrial replacement in human oocytes, and additionally, issues related to cross-generational epigenetic inheritance following IVF and germline genome editing. The resulting paper represents a consensus of both professional societies involved.Peer reviewe

Bi-allelic variants in DAP3 result in reduced assembly of the mitoribosomal small subunit with altered apoptosis and a Perrault-syndrome-spectrum phenotype

\ua9 2024 The Author(s)The mitochondrial ribosome (mitoribosome) synthesizes 13 protein subunits of the oxidative phosphorylation system encoded by the mitochondrial genome. The mitoribosome is composed of 12S rRNA, 16S rRNA, and 82 mitoribosomal proteins encoded by nuclear genes. To date, variants in 12 genes encoding mitoribosomal proteins are associated with rare monogenic disorders and frequently show combined oxidative phosphorylation deficiency. Here, we describe five unrelated individuals with bi-allelic variants in death-associated protein 3 (DAP3), a nuclear gene encoding mitoribosomal small subunit 29 (MRPS29), with variable clinical presentations ranging from Perrault syndrome (sensorineural hearing loss and ovarian insufficiency) to an early childhood neurometabolic phenotype. Assessment of respiratory-chain function and proteomic profiling of fibroblasts from affected individuals demonstrated reduced MRPS29 protein amounts and, consequently, decreased levels of additional protein components of the mitoribosomal small subunit, as well as an associated combined deficiency of complexes I and IV. Lentiviral transduction of fibroblasts from affected individuals with wild-type DAP3 cDNA increased DAP3 mRNA expression and partially rescued protein levels of MRPS7, MRPS9, and complex I and IV subunits, demonstrating the pathogenicity of the DAP3 variants. Protein modeling suggested that DAP3 disease-associated missense variants can impact ADP binding, and in vitro assays demonstrated that DAP3 variants can consequently reduce both intrinsic and extrinsic apoptotic sensitivity, DAP3 thermal stability, and DAP3 GTPase activity. Our study presents genetic and functional evidence that bi-allelic variants in DAP3 result in a multisystem disorder of combined oxidative phosphorylation deficiency with pleiotropic presentations, consistent with mitochondrial dysfunction

Bi-allelic variants in MRPL49 cause variable clinical presentations, including sensorineural hearing loss, leukodystrophy, and ovarian insufficiency

Combined oxidative phosphorylation deficiency (COXPD) is a rare multisystem disorder that is clinically and genetically heterogeneous. Genome sequencing identified bi-allelic MRPL49 variants in individuals from nine unrelated families with presentations ranging from Perrault syndrome (primary ovarian insufficiency and sensorineural hearing loss) to severe childhood onset of leukodystrophy, learning disability, microcephaly, and retinal dystrophy. Complexome profiling of fibroblasts from affected individuals revealed reduced levels of the small mitochondrial ribosomal subunits and a more pronounced reduction of the large mitochondrial ribosomal subunits. There was no evidence of altered mitoribosomal assembly. The reductions in levels of oxidative phosphorylation (OXPHOS) enzyme complexes I and IV are consistent with a form of COXPD associated with bi-allelic MRPL49 variants, expanding the understanding of how disruption of the mitochondrial ribosomal large subunit results in multisystem phenotypes

Perrault Syndrome

Clinical characteristics: Perrault syndrome is characterized by sensorineural hearing loss (SNHL) in males and females and ovarian dysfunction in females. SNHL is bilateral and ranges from profound with prelingual (congenital) onset to moderate with early-childhood onset. When onset is in early childhood, hearing loss can be progressive. Ovarian dysfunction ranges from gonadal dysgenesis (absent or streak gonads) manifesting as primary amenorrhea to primary ovarian insufficiency (POI) defined as cessation of menses before age 40 years. Fertility in affected males is reported as normal (although the number of reported males is limited). Neurologic features described in some individuals with Perrault syndrome include learning difficulties and developmental delay, cerebellar ataxia, and motor and sensory peripheral neuropathy.Diagnosis/testing: The diagnosis of Perrault syndrome is based on the clinical findings of SNHL in men and women and ovarian dysfunction in women with a 46,XX karyotype. The diagnosis is confirmed by the presence of biallelic pathogenic variants in one of six genes (CLPP, ERAL1, HARS2, HSD17B4, LARS2, or TWNK); however, in approximately 60% of individuals with Perrault syndrome identified to date, a molecular diagnosis cannot be established.Management: Treatment of manifestations: Hearing loss should be assessed and treated by a multidisciplinary team including an audiologist and otolaryngologist. Possible interventions for those with hearing loss include special educational resources, hearing aids, vibrotactile devices, and cochlear implantation. Cochlear implantation is an option for children older than 12 months with severe-to-profound hearing loss. Primary amenorrhea is treated in adolescents in collaboration with a pediatric endocrinologist in the usual manner, first to induce puberty and then to mimic the menstrual cycle and maintain bone health. Assisted reproduction through in vitro fertilization using donor eggs is a consideration for women with gonadal dysgenesis; oocyte cryopreservation can be considered in women at risk for POI. Surveillance: Routine audiologic assessments when hearing loss is mild to moderate; no follow up or audiologic assessments when hearing loss is profound. For children with hearing impairment: monitor development For women with primary amenorrhea: during induction of puberty, follow up every three months for staging of pubertal development and adjustment of estrogen dose. For women on maintenance estrogen replacement therapy: annual follow up as well as assessment of bone density approximately every five years. Agents/circumstances to avoid: Avoid: ototoxic medication (e.g., aminoglycosides) if alternative medications are available; exposure to loud noise, which can exacerbate hearing loss. Evaluation of relatives at risk: It is appropriate to evaluate the older and younger sibs of a proband in order to identify as early as possible those who would benefit from early interventions (e.g., in young children with profound hearing loss; estrogen replacement to facilitate pubertal development in females with ovarian involvement; and potential oocyte cryopreservation if POI is an issue).Genetic counseling: Perrault syndrome is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. When the pathogenic variants in the family are known, carrier testing for at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible

A Non-Adaptive Combinatorial Group Testing Strategy to Facilitate Healthcare Worker Screening During the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Outbreak

AbstractBackgroundRegular SARS-CoV-2 testing of healthcare workers (HCWs) has been proposed to prevent healthcare facilities becoming persistent reservoirs of infectivity. Using monoplex testing, widespread screening would be prohibitively expensive, and throughput may not meet demand. We propose a non-adaptive combinatorial (NAC) group-testing strategy to increase throughput and facilitate rapid turnaround via a single round of testing.MethodsNAC matrices were constructed for sample sizes of 700, 350 and 250 with replicates of 2, 4 and 5, respectively. Matrix performance was tested by simulation under different SARS-CoV-2 prevalence scenarios of 0.1-10%, with each simulation ran for 10,000 iterations. Outcomes included the proportions of re-tests required and the proportion of true negatives identified. NAC matrices were compared to Dorfman Sequential (DS) approaches. A web application (www.samplepooling.com) was designed to decode results.FindingsNAC matrices performed well at low prevalence levels with an average number of 585 tests saved per assay in the n=700 matrix at a 1% prevalence. As prevalence increased, matrix performance deteriorated with n=250 most tolerant. In simulations of low to medium (0.1%-3%) prevalence levels all NAC matrices were superior, as measured by fewer repeated tests required, to the DS approaches. At very high prevalence levels (10%) the DS matrix was marginally superior, however both group testing approaches performed poorly at high prevalence levels.InterpretationThis testing strategy maximises the proportion of samples resolved after a single round of testing, allowing prompt return of results to staff members. Using the methodology described here, laboratories can adapt their testing scheme based on required throughput and the current population prevalence, facilitating a data-driven testing strategy.FundingNone to Declare</jats:sec

Diagnosing and Preventing Hearing Loss in the Genomic Age

© The Author(s) 2019. Over the past two decades, significant technological advances have facilitated the identification of hundreds of genes associated with hearing loss. Variants in many of these genes result in severe congenital hearing loss with profound implications for the affected individual and their family. This review collates these advances, summarizing the current state of genomic knowledge in childhood hearing loss. We consider how current and emerging genetic technologies have the potential to alter our approach to the management and diagnosis of hearing loss. We review approaches being taken to ensure that these discoveries are used in clinical practice to detect genetic hearing loss as soon as possible to reduce unnecessary investigations, provide information about reproductive risks, and facilitate regular follow-up and early treatment. We also highlight how rapid sequencing technology has the potential to identify children susceptible to antibiotic-induced hearing loss and how this adverse reaction can be avoided