Genotype-phenotype correlation analysis in GNE myopathy
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Genotype-phenotype distinction
Compound heterozygosity
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is included in many newborn screening programmes worldwide. In addition to the prevalent mutation c.985A>G in the ACADM gene, potentially mild mutations like c.199T>C are frequently found in screening cohorts. There is ongoing discussion whether this mutation is associated with a clinical phenotype.In 37 MCADD patients detected by newborn screening, biochemical phenotype (octanoylcarnitine (C8), ratios of C8 to acetylcarnitine (C2), decanoylcarnitine (C10) and dodecanoylcarnitine (C12) at screening and confirmation) and clinical phenotype (inpatient emergency treatment, metabolic decompensations, clinical assessments, psychometric tests) were assessed in relation to genotype.16 patients were homozygous for c.985A>G (group 1), 11 compound heterozygous for c.199T>C and c.985A>G/another mutation (group 2) and 7 compound heterozygous for c.985A>G and mutations other than c.199T>C (group 3) and 3 carried neither c.985A>G nor c.199T>C but other known homozygous mutations (group 4). At screening C8/C2 and C8/C10, at confirmation C8/C2, C8/C10 and C8/C12 differed significantly between patients compound heterozygous for c.199T>C (group 2) and other genotypes. C8, C10 and C8/C2 at screening were strongly associated with time of sampling in groups 1 + 3 + 4, but not in group 2. Clinical phenotype did not differ between genotypes. Two patients compound heterozygous for c.199T>C and a severe mutation showed neonatal decompensation with hypoglycaemia.Biochemical phenotype differs between MCADD patients compound heterozygous for c.199T>C with a severe mutation and other genotypes. In patients detected by newborn screening, clinical phenotype does not differ between genotypes following uniform treatment recommendations. Neonatal decompensation can also occur in patients with the presumably mild mutation c.199T>C prior to diagnosis.
Compound heterozygosity
Genotype-phenotype distinction
Heterozygote advantage
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Compound heterozygous mutations, where two distinct mutated alleles are present within a particular gene, can give rise to the Bardet-Biedl syndrome (BBS). There is limited evidence suggesting that some compound heterozygotes can present with milder phenotypic characteristics than homozygotes. We report on the clinical characteristics of a 22-year-old Puerto Rican male who was compound heterozygous for the Bardet-Biedl syndrome type 1. Our patient had deteriorating visual acuity since early childhood. Clinical and ophthalmic examination revealed retinal dystrophy, polydactyly, and very mild learning disabilities. No additional systemic complications commonly observed in patients with the BBS were present. Allele-specific testing and DNA sequencing revealed compound heterozygous mutations (M390R and E549X) in the BBS1 gene. Our findings could suggest that patients who are compound heterozygotes for these specific BBS mutations can exhibit milder clinical signs than homozygous patients.
Compound heterozygosity
Bardet–Biedl Syndrome
Heterozygote advantage
Polydactyly
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Background: Frequency of dyslipidemia is on continuous rise in the developing countries including Pakistan. Many studies have shown that a raised LDL-cholesterol level, non-HDL cholesterol levels and decreased HDL-cholesterol levels are related with anraised risk of cardiovascular diseases and also certain muscle related symptoms. Aim: To find the frequency of statin-induced myopathy in dyslipidemic patients presenting in a tertiary care hospital. Methods It was a cross sectional study conducted among dyslipidemic patients presented at department of medicine and endocrinology, Unit-I Fatima Memorial hospital, Lahore. Non-probability consecutive sampling technique was used to select 230 dyslipidemic patients who met the inclusion criteria. Information was recorded on predesigned questionnaire regarding statin induced myopathy and socio-demographic variables. Results: In this study, the mean age statin induced myopathy respondents was 49.9±8.6 years while it was 49.9±9.4 years among not having statin induced myopathy.Statin induced myopathy was seen in 55 (23.9%) respondents while in 175 (76.1%) there was no statin induced myopathy. Gender among peripheral neuropathy showed that males were 42 and females were 13 in number; and among non-statin induced myopathy group there were 121 males and 54 females. Most of the middle income respondents were suffering from statin induced myopathy as compared to other income groups. Conclusion: This study reports an increased prevalence of statin induced myopathy among dyslipidemic patients. Male respondents were more in number than females but both had shown insignificant relationship with statin induced myopathy. The age>45 years of the respondents showed significant statistical difference with gender. Keywords: Statin Induced Myopathy, Dyslipidemia, Lahore
Dyslipidemia
Cross-sectional study
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Compound heterozygosity
Genotype-phenotype distinction
Heterozygote advantage
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Abstract Human nude SCID is a rare autosomal recessive inborn error of immunity (IEI) characterized by congenital athymia, alopecia, and nail dystrophy. Few cases have been reported to date. However, the recent introduction of newborn screening for IEIs and high-throughput sequencing has led to the identification of novel and atypical cases. Moreover, immunological alterations have been recently described in patients carrying heterozygous mutations. The aim of this paper is to describe the extended phenotype associated with FOXN1 homozygous, compound heterozygous, or heterozygous mutations. We collected clinical and laboratory information of a cohort of 11 homozygous, 2 compound heterozygous, and 5 heterozygous patients with recurrent severe infections. All, except one heterozygous patient, had signs of CID or SCID. Nail dystrophy and alopecia, that represent the hallmarks of the syndrome, were not always present, while almost 50% of the patients developed Omenn syndrome. One patient with hypomorphic compound heterozygous mutations had a late-onset atypical phenotype. A SCID-like phenotype was observed in 4 heterozygous patients coming from the same family. A spectrum of clinical manifestations may be associated with different mutations. The severity of the clinical phenotype likely depends on the amount of residual activity of the gene product, as previously observed for other SCID-related genes. The severity of the manifestations in this heterozygous family may suggest a mechanism of negative dominance of the specific mutation or the presence of additional mutations in noncoding regions.
Compound heterozygosity
Heterozygote advantage
Dominance (genetics)
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Compound heterozygous mutations, where two distinct mutated alleles are present within a particular gene, can give rise to the Bardet-Biedl syndrome (BBS). There is limited evidence suggesting that some compound heterozygotes can present with milder phenotypic characteristics than homozygotes. We report on the clinical characteristics of a 22-year-old Puerto Rican male who was compound heterozygous for the Bardet-Biedl syndrome type 1. Our patient had deteriorating visual acuity since early childhood. Clinical and ophthalmic examination revealed retinal dystrophy, polydactyly, and very mild learning disabilities. No additional systemic complications commonly observed in patients with the BBS were present. Allele-specific testing and DNA sequencing revealed compound heterozygous mutations (M390R and E549X) in the BBS1 gene. Our findings could suggest that patients who are compound heterozygotes for these specific BBS mutations can exhibit milder clinical signs than homozygous patients.
Compound heterozygosity
Bardet–Biedl Syndrome
Heterozygote advantage
Polydactyly
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We report a 9-year-old Chinese girl with congenital thrombotic thrombocytopenic purpura found to be a compound heterozygote for 2 pathogenic variants in the ADAMTS13 gene, including a novel variation. The girl suffered from recurrent, life-threatening episodes of thrombocytopenia and hemolysis, and laboratory testing showed ADAMST13 enzyme activity of <5%. Sequencing of the ADAMTS13 gene revealed a previously reported missense variant, c.1787C>T (p.Ala596Val), and a novel duplication defined as c.1007_1025dup19 (p.Asp343Leufs*53); the duplication is predicted to result in a premature stop codon and protein truncation. We propose that this novel variant is partly responsible for the patient’s early-onset and severe phenotype.
Compound heterozygosity
ADAMTS13
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We report a case of 2 sisters in their 20s with genetically confirmed UDP-N-acetylglucoasmine 2-epimerase/N-acetylmannosamine kinase myopathy along with muscle biopsy findings. Both patients described slowly progressive signs of distal-predominant weakness since adolescence that had been dismissed as "clumsiness." Exam and electrodiagnostic testing suggested a predominately distal myopathy. Muscle biopsy of the left tibialis anterior revealed rimmed vacuoles and, interestingly, also had characteristic features of a myofibrillar myopathy. Genetic testing confirmed a diagnosis of autosomal recessive GNE myopathy in both patients. GNE myopathy has not typically been considered a myofibrillar myopathy, but this case raises possibilities worthy of further exploration. It is possible that the unique combination of pathogenic alleles in GNE reported here has led to a novel form of GNE myopathy with muscle biopsy showing characteristic features of GNE myopathy and myofibrillar myopathy. The other possibility is that myofibrillar myopathy may be a more common feature of GNE myopathies than classically described.
Myofibril
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Background Although statin-related myopathy is a common adverse event, diagnostic criteria and standard treatments have not yet been established. Furthermore, statin-related myopathy is a major concern because of intolerance and discontinuation of statin agents. Objective To elucidate the clinical characteristics of statin-related myopathy, we retrospectively studied 20 patients with hyperlipidemia who had been receiving statin agents. Results Five of 20 patients developed creatine kinase (CK) elevation, and 2 of these 5 patients developed statin-related myopathy. Statistical analysis of the differences between the CK-high and CK-normal groups revealed that a relatively younger age and hepatic dysfunction were risk factors for statin-related myopathy. Among the 20 patients administered statin agents, patients taking atorvastatin (cytochrome P450 inhibitor) had a high tendency for CK elevation (3/7 patients). The 2 patients with statin-related myopathy were discontinued atorvastatin for four weeks. Statin-related myopathy had gradually resolved. Subsequently, we administered pitavstatin (non-cytochrome P450 inhibitor) for 2 cases. This treatment led to the inhibition and resolution of statin-related myopathy. In the 3 patients with CK elevation without myopathy, we did not change the statin agent. However, these patients did not develop statin-related myopathy. Conclusion We present the detailed clinical characteristics of 5 patients with CK elevation and address our experiences with the control of side effect. This case-oriented study should be helpful to the physicians who directly care for statin-related myopathy patients, and may provide a future direction for performing a more efficient control.
Discontinuation
myalgia
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Combined Oxidative Phosphorylation Deficiency 23 (COXPD23) caused by mutations in GTPBP3 gene is a rare mitochondrial disease, and this disorder identified from the Chinese population has not been described thus far. Here, we report a case series of three patients with COXPD23 caused by GTPBP3 mutations, from a severe to a mild phenotype. The main clinical features of these patients include lactic acidosis, myocardial damage, and neurologic symptoms. Whole genome sequencing and targeted panels of candidate human mitochondrial genome revealed that patient 1 was a compound heterozygote with novel mutations c.413C > T (p. A138V) and c.509_510del (p. E170Gfs ∗ 42) in GTPBP3 . Patient 2 was a compound heterozygote with novel mutations c.544G > T (p. G182X) and c.785A > C (p.Q262P), while patient 3 was a compound heterozygote with a previously reported mutation c.424G > A (p.E142K) and novel mutation c.785A > C (p.Q262P). In conclusion, we first describe three Chinese individuals with COXPD23, and discuss the genotype-phenotype correlations of GTPBP3 mutations. Our findings provide novel information in the diagnosis and genetic counseling of patients with mitochondrial disease.
Compound heterozygosity
Heterozygote advantage
Genotype-phenotype distinction
Mitochondrial disease
Lactic acidosis
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