Genotype-phenotype associations in CRB1 bi-allelic patients: a novel mutation, a systematic review and meta-analysis
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ABSTRACT:
SUBMITTER: Daher A
PROVIDER: S-EPMC11017593 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:Recessive SH3TC2 variants cause Charcot-Marie-Tooth disease type 4C (CMT4C). CMT4C is typically a sensorimotor demyelinating polyneuropathy, marked by early onset spinal deformities, but its clinical characteristics and severity are quite variable. Clear relationships between pathogenic variants and the spectrum of disease manifestations are to date lacking. Gene replacement therapy has been shown to ameliorate the phenotype in a mouse model of CMT4C, emphasizing the need for natural history studies to inform clinical trial readiness. Data, including both genetic information and clinical characteristics, were compiled from the longitudinal, prospective dataset of the Inherited Neuropathy Consortium, a member of the Rare Diseases Clinical Research Network (INC-RDCRN). The Charcot Marie Tooth Neuropathy Score (CMTNS), Examination Score (CMTES) and the Rasch-weighted CMTES (CMTES-R) were used to describe symptoms, neurological examinations and neurophysiological characteristics. Standardized response means were calculated at yearly intervals and a mixed model for repeated measures was used to estimate the change in CMTES and CMTES-R over time. Fifty-six individuals (59% female), median age 27 years (range 2-67 years) with homozygous or compound heterozygous variants in SH3TC2 were identified, including 34 unique variants, 14 of which have not previously been published. Twenty-eight participants had longitudinal data available. While there was no significant difference in the CMTES in those with protein truncating versus non-protein truncating variants, there were significant differences in the mean ulnar nerve compound muscle action potential amplitude, the mean radial sensory nerve action potential amplitude, and in the prevalence of scoliosis, suggesting the possibility of a milder phenotype in individuals with one or two non-protein-truncating variants. Overall, the mean value of the CMTES was 13, reflecting moderate clinical severity. There was a high rate of scoliosis (81%), scoliosis surgery (36%), and walking difficulty (94%) among study participants. The CMTES and CMTES-R appeared moderately responsive to change over extended follow-up, demonstrating a standardized response mean of 0.81 standard deviation units or 0.71 standard deviation units, respectively, over 3 years. Our analysis represents the largest cross-sectional and only longitudinal study to date, of the clinical phenotype of both adults and children with CMT4C. With the promise of upcoming genetic treatments, these data will further define the natural history of the disease and inform study design in preparation for clinical trials.
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Project description:BackgroundAlström syndrome (ALMS; #203800) is an ultrarare monogenic recessive disease. This syndrome is associated with variants in the ALMS1 gene, which encodes a centrosome-associated protein involved in the regulation of several ciliary and extraciliary processes, such as centrosome cohesion, apoptosis, cell cycle control and receptor trafficking. The type of variant associated with ALMS is mostly complete loss-of-function variants (97%) and they are mainly located in exons 8, 10 and 16 of the gene. Other studies in the literature have tried to establish a genotype-phenotype correlation in this syndrome with limited success. The difficulty in recruiting a large cohort in rare diseases is the main barrier to conducting this type of study.MethodsIn this study we collected all cases of ALMS published to date. We created a database of patients who had a genetic diagnosis and an individualised clinical history. Lastly, we attempted to establish a genotype-phenotype correlation using the truncation site of the patient's longest allele as a grouping criteria.ResultsWe collected a total of 357 patients, of whom 227 had complete clinical information, complete genetic diagnosis and meta-information on sex and age. We have seen that there are five variants with high frequency, with p.(Arg2722Ter) being the most common variant, with 28 alleles. No gender differences in disease progression were detected. Finally, truncating variants in exon 10 seem to be correlated with a higher prevalence of liver disorders in patients with ALMS.ConclusionPathogenic variants in exon 10 of the ALMS1 gene were associated with a higher prevalence of liver disease. However, the location of the variant in the ALMS1 gene does not have a major impact on the phenotype developed by the patient.
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Project description:BackgroundMicrotia is a congenital ear malformation that can occur as isolated microtia or as part of a syndrome. The etiology is currently poorly understood, although there is strong evidence that genetics has a role in the occurrence of microtia. This systematic review aimed to determine the genes involved and the abnormalities in microtia patients' head and neck regions.MethodsWe used seven search engines to search all known literature on the genetic and phenotypic variables associated with the development or outcome of microtia. The identified publications were screened and selected based on inclusion and exclusion criteria and assessed for methodological quality using the Joanna Briggs Institute (JBI) critical appraisal tools. We found 40 papers in this systematic review with phenotypic data in microtia involving 1459 patients and 30 articles containing genetic data involved in microtia.ResultThe most common accompanying phenotype of all microtia patients was external ear canal atresia, while the most common head and neck abnormalities were the auricular, mental, and oral regions. The most common syndrome found was craniofacial microsomia syndrome. In the syndromic microtia group, the most common genes were TCOF1 (43.75%), SIX2 (4.69%), and HSPA9 (4.69%), while in the non-syndromic microtia group, the most frequently found gene was GSC exon 2 (25%), FANCB (16.67%), HOXA2 (8.33%), GSC exon 3 (8.33%), MARS1 (8.33%), and CDT1 (8.33%).ConclusionsOur systematic review shows some genes involved in the microtia development, including TCOF1, SIX2, HSPA9, GSC exon 2, FANCB, HOXA2, GSC exon 3, MARS1, and CDT1 genes. We also reveal a genotype-phenotype association in microtia. In addition, further studies with more complete and comprehensive data are needed, including patients with complete data on syndromes, phenotypes, and genotypes.
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Project description:Brittle and "tiger-tail" hair is the diagnostic hallmark of trichothiodystrophy (TTD), a rare recessive disease associated with a wide spectrum of clinical features including ichthyosis, intellectual disability, decreased fertility, and short stature. As a result of premature abrogation of terminal differentiation, the hair is brittle and fragile and contains reduced cysteine content. Hypersensitivity to UV light is found in about half of individuals with TTD; all of these individuals harbor bi-allelic mutations in components of the basal transcription factor TFIIH, and these mutations lead to impaired nucleotide excision repair and basal transcription. Different genes have been found to be associated with non-photosensitive TTD (NPS-TTD); these include MPLKIP (also called TTDN1), GTF2E2 (also called TFIIEβ), and RNF113A. However, a relatively large group of these individuals with NPS-TTD have remained genetically uncharacterized. Here we present the identification of an NPS-TTD-associated gene, threonyl-tRNA synthetase (TARS), found by next-generation sequencing of a group of uncharacterized individuals with NPS-TTD. One individual has compound heterozygous TARS variants, c.826A>G (p.Lys276Glu) and c.1912C>T (p.Arg638∗), whereas a second individual is homozygous for the TARS variant: c.680T>C (p.Leu227Pro). We showed that these variants have a profound effect on TARS protein stability and enzymatic function. Our results expand the spectrum of genes involved in TTD to include genes implicated in amino acid charging of tRNA, which is required for the last step in gene expression, namely protein translation. We previously proposed that some of the TTD-specific features derive from subtle transcription defects as a consequence of unstable transcription factors. We now extend the definition of TTD from a transcription syndrome to a "gene-expression" syndrome.
| S-EPMC6698936 | biostudies-literature
Project description:PurposeThe purpose of this study was to investigate the genotypic and phenotypic characteristics of CRB1-associated early onset retinal dystrophy (CRB1-eoRD) and retinal architecture by swept-source optical coherence tomography (SS-OCT).MethodsEleven probands with CRB1-eoRD were recruited. Clinical information, genetic analysis, and comprehensive ophthalmic examinations including SS-OCT and SS-OCT angiography (SS-OCTA) were conducted.ResultsA total of 81.8% (9/11) of CRB1-eoRD presented as Leber congenital amaurosis (LCA). Common clinical manifestations included coin-like yellow-white retinal spots (20/22, 90.9%) and para-arteriolar retinal pigment epithelial retention (12/22, 54.5%). Nineteen different CRB1 variants were detected in our case series, including 12 missense, 3 frameshifts, 3 nonsense, and 1 splicing. Of them, 12 variants had been reported, and 7 were novel. SS-OCT showed thinner central macula (the LCA group, P < 0.0001), thicker total retina (P < 0.0001), thinner outer retina (P < 0.05), and thicker inner retina (P < 0.0001) compared with the healthy control. The inner/outer (I/O) retina thickness ratio of CRB1-eoRD was 3.0, higher than the healthy control of 1.2 and other inherited retinal diseases (IRDs) of 2.2 (P < 0.0001 and P = 0.0027, respectively). SS-OCTA revealed an increased vascular density and perfusion area of the superficial vascular complex and deep vascular complex in CRB1-eoRD.ConclusionsLCA emerges as a frequently occurring phenotype in CRB1-eoRD. The unique features of SS-OCT and SS-OCTA are illustrated, and the novel biomarker, I/O ratio, may facilitate early diagnosis. The insights gained from this study hold significant value in determining the treatment window for potential forthcoming CRB1 gene therapy.
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Project description:BackgroundOligoasthenoteratozoospermia (OAT) is a widespread cause of male infertility. One of the usual clinical manifestations of OAT is multiple morphological abnormalities of the sperm flagella (MMAF), which are frequently associated with mutations and defects in the dynein family. However, the relationship between the newly identified Dynein Axonemal Heavy Chain 3 (DNAH3) mutation and oligonasthenospermia in humans has not yet been established.MethodsWhole exome sequencing, pathogenicity analysis, and species conservation analysis of mutation sites were conducted on two patients from different unrelated families with DNAH3 mutations. We identified representative mutation sites and predicted the protein structure following these mutations. The sperm characteristics of the two patients with DNAH3 mutations were verified using Papanicolaou staining, scanning electron microscopy, and transmission electron microscopy. Additionally, mRNA and protein levels were assessed through RT-qPCR and Western blotting.ResultsThe biallelic mutations in the first progenitor included a heterozygous deletion and insertion, c.6535_6536 delinsAC (to infect mutation (p.Asp2179Thr), and stop codon premutation, c.3249G > A (p.Trp1083Ter). In Family II, the patient (P2) harbored a DNAH3 heterozygous missense mutation, c. 10439G> A(p.Arg3480Gln), along with a stop codon premutation, (c.10260G > A; p.Trp3420Ter). Patients with premature termination of transcription or translation due to DNAH3 mutations exhibit OAT phenotypes, including fibrous sheath dysplasia and multiple tail malformations. We identified the representative sites after mutation, predicted the protein structure, and assessed changes in the protein levels of DNAH3 and related genes following mutations. Notably,a significant reduction in DNAH3 protein expression was validated in these patients. We may explore in the future how DNAH3 affects sperm motility and quality through regulatory mechanisms involving protein structural changes.ConclusionNovel biallelic mutations in DNAH3, especially those resulting in a premature stop codon, may alter protein expression, structure, and active site, leading to spermatogenic failure and potentially inducing OAT. The discovery of new mutations in DNAH3 may be the key to the diagnosis and treatment of OAT.
| S-EPMC11586517 | biostudies-literature
Project description:Genotype-phenotype Associations in Pediatric Cardiomyopathy
| PRJNA1047225 | ENA
Project description:Genotype-phenotype Associations in Pediatric Cardiomyopathy
| PRJNA1047206 | ENA
Project description:Developmental and epileptic encephalopathies (DEEs) have high genetic heterogeneity, and DEE due to the potassium voltage-gated channel subfamily C member 2 (KCNC2) variant remains poorly understood, given the scarcity of related case studies. We report on two unrelated Chinese patients, an 11-year-old boy and a 5-year-old girl, diagnosed with global developmental delay (GDD), intellectual disability (ID), and focal impaired awareness seizure characterized by generalized spike and wave complexes on electroencephalogram (EEG) in the absence of significant brain lesions. Whole-exome sequencing (WES) and electrophysiological analysis were performed to detect genetic variants and evaluate functional changes of the mutant KCNC2, respectively. Importantly, we identified a novel gain-of-function KCNC2 variant, R405G, in both patients. Previously reported variants, V471L, R351K, T437A, and T437N, and novel R405G were found in multiple unrelated patients with DEE, showing consistent genotype-phenotype associations. These findings emphasize that the KCNC2 gene is causative for DEE and facilitates treatment and prognosis in patients with DEE due to KCNC2 mutations.
| S-EPMC9453199 | biostudies-literature
Project description:ObjectiveTo systematically review the relationship between genotypes and clinical phenotypes of Familial exudative vitreoretinopathy (FEVR) to support risk estimation and therapeutic decisions.DesignSystematic review with meta-analysis.Data sourcesThe data of our study were collected from PubMed, Embase, Web of Science, Cochrane, CBM, China National Knowledge Infrastructure (CNKI), WAN FANG and VIP databases since inception to August 2021.ResultsA total of 3257 patients from 32 studies were included according to the inclusion and exclusion criteria. Among all the cases, the mutation frequencies of LRP5, FZD4, NDP, TSPAN12, ZNF408 and KIF11 were 13.6%, 11.5%, 4.6%, 6.7%, 1.6%, and 5.7%, respectively. We found that the patients with NDP and FZD4 suffer more severe symptoms, among which 86.4% patients of NDP and 78.6% patients of FZD4 were in the advanced stage of FEVR. Retinal detachment is the most frequent symptom with patients of LRP5 and NDP mutations, accounting for 51.9% and 64.5%, respectively. For the patients with the mutation of TSPAN12, retinal fold is the most common clinical manifestation, and suffer the mildest clinical phenotypes compared with the other three genes.ConclusionThe results of the meta-analysis indicate that different types of genetic mutations occur at different frequencies. In addition, the clinical manifestations of FEVR are related to the type of gene mutation. Therefore, targeted treatment strategies and follow-up recommendations should be adopted for different pathogenic genes of FEVR.
| S-EPMC9278778 | biostudies-literature