Project description:Presented here are five members of a family that was ascertained from an isolated, consanguineous, indigenous Amerindian community in Colombia that was affected with calpain 3-related, limb-girdle muscular dystrophy type R1. These patients are homozygous for a unique and novel deletion of four bases (TGCC) in exon 3 of the calpain 3 gene (CAPN3) (NM_000070.2; NP_000061.1) (g.409_412del). The mutation site occurs at the CysPc protein domain, triggering a modified truncated protein structure and affecting motifs within the calpain-like thiol protease family (peptidase family C2) region. The patients reported here developed a very severe phenotype with primary contractures, spinal rigidity in the early stages of the disease, and bilateral talipes equinovarus (clubfoot) in the most affected patients who had the selective involvement of their extremities' distal muscles in a way that resembled Emery-Dreifuss syndrome. We recommend mandatory screening for calpainopathy in all patients with an Emery-Dreifuss-like syndrome or those presenting a non-congenital illness with primary contractures and who, because of other data, are suspected of having muscular dystrophy.
Project description:Ectodermal dysplasias (EDs) are a large and heterogeneous group of hereditary disorders characterized by abnormalities in structures of ectodermal origin. Incontinentia pigmenti (IP) is an ED characterized by skin lesions evolving over time, as well as dental, nail, and ocular abnormalities. Due to X-linked dominant inheritance IP symptoms can only be seen in female individuals while affected males die during development in utero. We observed a family of horses, in which several mares developed signs of a skin disorder reminiscent of human IP. Cutaneous manifestations in affected horses included the development of pruritic, exudative lesions soon after birth. These developed into wart-like lesions and areas of alopecia with occasional wooly hair re-growth. Affected horses also had streaks of darker and lighter coat coloration from birth. The observation that only females were affected together with a high number of spontaneous abortions suggested an X-linked dominant mechanism of transmission. Using next generation sequencing we sequenced the whole genome of one affected mare. We analyzed the sequence data for non-synonymous variants in candidate genes and found a heterozygous nonsense variant in the X-chromosomal IKBKG gene (c.184C>T; p.Arg62*). Mutations in IKBKG were previously reported to cause IP in humans and the homologous p.Arg62* variant has already been observed in a human IP patient. The comparative data thus strongly suggest that this is also the causative variant for the observed IP in horses. To our knowledge this is the first large animal model for IP.
Project description:Wilms' tumour suppressor gene-1 (WT1) plays a critical role in kidney development and function. Several WT1 mutations can occur in exons 7, 8 and 9 and they have been associated with Denys-Drash syndrome. WT1 mutations of intron 9 have been reported too and associated with Frasier syndrome. However, overlapping and incomplete forms of both the syndromes have been described. We report a novel sequence variant (c.1012A>T) of the WT1 gene in exon 6 (p.R338X) in a 18-year-old girl with a history of Wilms' tumour, minor gonadal changes and relatively late-onset nephropathy. WT1-related nephropathies should be suspected in every patient with proteinuria not associated to immunological changes when a congenital neoplasia or minor gonadal anomalies are present.
Project description:A highly variable phenotype characterized by thyroid, respiratory and neurological defects has been reported in an already established group of disorders namely NKX2.1-related disorders. We describe here the case of an infant with a novel mutation of the NKX2.1 gene characterized by mild clinical presentation. Aim of the study was to elucidate the genotype-phenotype correlation in our patient.We performed genetic analysis of the NKX2.1 gene in an infant with no neonatal respiratory distress and near-normal results at neonatal screening test for congenital hypothyroidism, choreoathetosis, ataxia and delayed independent walking.A novel mutation of the NKX2.1 gene has been identified, that is responsible for a mild framework of congenital hypothyroidism and neurological symptoms.The frequency of congenital hypothyroidism cases associated with NKX2.1 mutations is expected to be higher in a subgroup of patients, selected according to the neurological presentation. In these patients the analysis of NKX2.1 mutational status is recommended.
Project description:Four patients with adult-onset, disseminated mycobacterial infection had 5' UTR mutations in IKBKG without clear physical stigmata of NEMO deficiency. These mutations caused decreased levels of NEMO protein and Toll-like receptor driven cytokine production. Three patients died from disseminated disease. These mutations may be missed by whole exome sequencing.
Project description:Familial Mediterranean Fever (FMF), which is an autosomal recessive disease characterized by recurrent self-limiting fever, peritonitis, pleuritis, arthritis and erysipelas-like erythemas, has been common among ethnic groups such as Turkish, Armenian, Arabic and Jewish. The clinical presentation is caused by mutations in the MEFV gene encoding the Pyrin protein. In this study, we aimed to present a new mutation that has not been previously defined from the mutations in the MEFV gene which is responsible for the genetic pathology of familial Mediterranean fever and to evaluate the frequency of distribution of the MEFV gene mutation among different ethnic groups living in our region. In present retrospective study, a total of 2639 clinically suspected FMF patients who were referred to Hatay Mustafa Kemal University Hospital between 2010 and 2017 were recorded. MEFV gene mutations were observed using DNA sequence analysis. MEFV mutations were found in 2079 of the 2639 patients (78.7%) Among these patients 184 (6.97%) were homozygous, while 1365 (51.72%) were heterozygous. The most frequently observed mutation was R202Q (1319, 19.55%) followed by E148Q (n = 476, 7.05%), M694V (n = 439, 6.51%), V726A (n = 146, 2.16%) and M680I (n = 135, 2%). In a case clinically diagnosed as FMF, a new mutation called S145G (p. Ser145Gly, c.433A > G) was identified in exon 2 of the MEFV gene. Besides, addition of a new pathogenic MEFV variant to the literature, the relationship between the FMF clinic and homozygous form of R202Q, which was previously considered as a polymorphism, was highlighted.
Project description:Gnathodiaphyseal dysplasia (GDD; OMIM #166260) is an ultra-rare autosomal dominant disorder caused by heterozygous mutation in the anoctamin 5 (ANO5) gene and features fibro-osseous lesions of the jawbones, bone fragility with recurrent fractures, and bowing/sclerosis of tubular bones. The physiologic role of ANO5 is unknown. We report a 5-year-old boy with a seemingly atypical and especially severe presentation of GDD and unique ANO5 mutation. Severe osteopenia was associated with prenatal femoral fractures, recurrent postnatal fractures, and progressive bilateral enlargement of his maxilla and mandible beginning at ~2months-of-age that interfered with feeding and speech and required four debulking operations. Histopathological analysis revealed benign fibro-osseous lesions resembling cemento-ossifying fibromas of the jaw without psammomatoid bodies. A novel, de novo, heterozygous, missense mutation was identified in exon 15 of ANO5 (c.1553G>A; p.Gly518Glu). Our findings broaden the phenotypic and molecular spectra of GDD. Fractures early in life with progressive facial swelling are key features. We assessed his response to a total of 7 pamidronate infusions commencing at age 15months. Additional reports must further elucidate the phenotype, explore any genotype-phenotype correlation, and evaluate treatments.
Project description:BackgroundNF-κB essential modulator (NEMO), encoded by IKBKG, is necessary for activation of the ubiquitous transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Animal studies suggest NEMO is required for NF-κB mediated bone homeostasis, but this has not been thoroughly studied in humans. IKBKG loss-of-function mutation causes incontinentia pigmenti (IP), a rare X-linked disease featuring linear hypopigmentation, alopecia, hypodontia, and immunodeficiency. Single case reports describe osteopetrosis (OPT) in boys carrying hypomorphic IKBKG mutations.MethodWe studied the bone phenotype in women with IP with evaluation of radiographs of the spine and non-dominant arm and leg; lumbar spine and femoral neck aBMD using DXA; μ-CT and histomorphometry of trans-iliac crest biopsy specimens; bone turnover markers; and cellular phenotype in bone marrow skeletal (stromal) stem cells (BM-MSCs) in a cross-sectional, age-, sex-, and BMI-matched case-control study. X-chromosome inactivation was measured in blood leucocytes and BM-MSCs using a PCR method with methylation of HpaII sites. NF-κB activity was quantitated in BM-MSCs using a luciferase NF-κB reporter assay.ResultsSeven Caucasian women with IP (age: 24-67 years and BMI: 20.0-35.2 kg/m2) and IKBKG mutation (del exon 4-10 (n = 4); c.460C>T (n = 3)) were compared to matched controls. The IKBKG mutation carriers had extremely skewed X-inactivation (>90:10%) in blood, but not in BM-MSCs. NF-κB activity was lower in BM-MSCs from IKBKG mutation carriers (n = 5) compared to controls (3094 ± 679 vs. 5422 ± 1038/μg protein, p < 0.01). However, no differences were identified on skeletal radiographics, aBMD, μ-architecture of the iliac crest, or bone turnover markers. The IKBKG mutation carriers had a 1.7-fold greater extent of eroded surfaces relative to osteoid surfaces (p < 0.01), and a 2.0-fold greater proportion of arrested reversal surface relative to active reversal surface (p < 0.01).ConclusionUnlike mutation-positive males, the IKBKG mutation-positive women did not manifest OPT.
Project description:Although Attention Deficit Hyperactivity Disorder (ADHD) is recognised to be a familial and heritable disorder, little is known about the broader family characteristics of having a parent with ADHD problems. The main aim of this study was to investigate the relationship between parent ADHD problems, child clinical presentation and family functioning in a sample of children with ADHD. The sample consisted of 570 children with ADHD. Child psychopathology was assessed using a semi-structured diagnostic interview. Questionnaires were used to assess ADHD in the parents (childhood and current symptoms), family environment and mother/father-child relationship. Parental ADHD problems were associated with a range of adverse clinical outcomes in children with no difference in effects for mothers with ADHD problems compared to fathers with ADHD problems. Levels of maternal hostility were higher in families where mothers had ADHD problems, but reduced where fathers had ADHD problems. Parental ADHD problems index higher risk for more severe clinical presentation of ADHD in children and higher levels of family conflict (where there are maternal but not paternal ADHD problems). This study highlights that children with more severe behavioural symptoms are more likely to have a parent with persistent ADHD which has important implications when considering treatment and intervention strategies.
Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Understanding the influence of mutations in the SARS-CoV-2 gene on clinical outcomes is critical for treatment and prevention. Here, we analyzed all high-coverage complete SARS-CoV-2 sequences from GISAID database from January 1, 2020, to January 1, 2021, to mine the mutation hotspots associated with clinical outcome and developed a model to predict the clinical outcome in different epidemic strains. Exploring the cause of mutation based on RNA-dependent RNA polymerase (RdRp) and RNA-editing enzyme, mutation was more likely to occur in severe and mild cases than in asymptomatic cases, especially A > G, C > T, and G > A mutations. The mutations associated with asymptomatic outcome were mainly in open reading frame 1ab (ORF1ab) and N genes; especially R6997P and V30L mutations occurred together and were correlated with asymptomatic outcome with high prevalence. D614G, Q57H, and S194L mutations were correlated with mild and severe outcome with high prevalence. Interestingly, the single-nucleotide variant (SNV) frequency was higher with high percentage of nt14408 mutation in RdRp in severe cases. The expression of ADAR and APOBEC was associated with clinical outcome. The model has shown that the asymptomatic percentage has increased over time, while there is high symptomatic percentage in Alpha, Beta, and Gamma. These findings suggest that mutation in the SARS-CoV-2 genome may have a direct association with clinical outcomes and pandemic. Our result and model are helpful to predict the prevalence of epidemic strains and to further study the mechanism of mutation causing severe disease.