Medium-Chain Acyl-CoA Dehydrogenase Deficiency: Evaluation of Genotype-Phenotype Correlation in Patients Detected by Newborn Screening
Gwendolyn GramerGisela HaegeJunmin Fang‐HoffmannGeorg F. HoffmannClaus R. BartramKatrin HinderhoferPeter BurgardMartin Lindner
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Abstract:
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.Keywords:
Compound heterozygosity
Genotype-phenotype distinction
Heterozygote advantage
Objective: To investigate the prevalence and analyze the clinical hematological data of β-thalassemia(β-thal) CD41-42 (-TCTT) heterozygote(β41-42 heterozygote) compound deletional α-thal in this area. Methods: α-thal genes and β-thal genes were detected by single-tube complex PCR and reverse dot blotting(RDB), respectively. The analysis of blood corpuscle and the other thal screening tests were generally used. Results : 8 cases were identified to compound with α-thal in 144 β 41-42 heterozygote cases, including 7 cases (4.9%) compound α-thal-1(αα/-- SEA ) and 1 case(0.69%) compound deletional HbH gene(-α 3.7 /-- SEA ). The MCV of the 7 cases compoundα-thal-1 were all higher than the average MCV (63.53fl) of the 136 β 41-42 heterozygote cases. The HbH section couldn't be found in the case which compounds the HbH gene by the pH8.6 and the pH 6.5 Hemoglobin electrophoresis method. Conclusions: We can't only depend on the clinical symptoms and the routine lab examination results on diagnosing the β 41-42 heterozygote compound α-thal patients.
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Abstract Homozygosity for the C282Y mutation in the HFE gene is strongly associated with hereditary hemochromatosis. More than one subject out of 10 in the general population is a heterozygote for the C282Y mutation. In this study, we address whether or not conclusions drawn from HLA‐based family studies regarding the expression of heterozygous hemochromatosis are applicable to C282Y heterozygotes. The correlation between HLA‐inferred and HFE genotypes and the variation of serum iron tests according to HFE genotype and other factors were studied in persons from well‐characterized hemochromatosis pedigrees. Subjects were tested for both C282Y and H63D mutations. The following factors were studied: age, sex, alcohol consumption, body mass index, liver function tests, serum lipids and glucose, serum iron, transferrin saturation, and ferritin. HLA‐inferred heterozygotes were C282Y heterozygotes in only 70% and compound heterozygotes (i.e., heterozygotes for both C282Y and H63D) in 20%. C282Y heterozygotes did not differ from wild type homozygotes in terms of serum iron tests. Only compound heterozygotes presented with slightly increased transferrin saturation. On the other hand, increased serum ferritin was strongly associated with overweight or lipidic or glucose abnormalities. C282Y heterozygotes selected from family studies do not have greater serum iron tests than wild type homozygotes, except for compound heterozygotes, and therefore should not require special followup. The discovery of abnormal iron tests in a C282Y heterozygote should lead to workup for other causes of iron overload. © 2002 Wiley‐Liss, Inc.
Heterozygote advantage
Compound heterozygosity
Transferrin saturation
Hereditary hemochromatosis
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Fibrillin
Compound heterozygosity
Heterozygote advantage
Ectopia lentis
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While Parkinson disease (PD) is consistently associated with impaired olfaction, one study reported better olfaction among Parkin mutation carriers than noncarriers. Whether olfaction differs between Parkin mutation heterozygotes and carriers of 2 Parkin mutations (compound heterozygotes) is unknown.To assess the relationship between Parkin genotype and olfaction in PD probands and their unaffected relatives.We administered the University of Pennsylvania Smell Identification Test (UPSIT) to 44 probands in the Consortium on Risk for Early-Onset Parkinson Disease study with PD onset ≤50 years (10 Parkin mutation heterozygotes, 9 compound heterozygotes, 25 noncarriers) and 80 of their family members (18 heterozygotes, 2 compound heterozygotes, 60 noncarriers). In the probands, linear regression was used to assess the association between UPSIT score (outcome) and Parkin genotype (predictor), adjusting for covariates. Among family members without PD, we compared UPSIT performance in heterozygotes vs noncarriers using generalized estimating equations, adjusting for family membership, age, gender, and smoking.Among probands with PD, compound heterozygotes had higher UPSIT scores (31.9) than heterozygotes (20.1) or noncarriers (19.9) (p < 0.001). These differences persisted after adjustment for age, gender, disease duration, and smoking. Among relatives without PD, UPSIT performance was similar in heterozygotes (32.5) vs noncarriers (32.4), and better than in heterozygotes with PD (p = 0.001).Olfaction is significantly reduced among Parkin mutation heterozygotes with PD but not among their heterozygous relatives without PD. Compound heterozygotes with PD have olfaction within the normal range. Further research is required to assess whether these findings reflect different neuropathology in Parkin mutation heterozygotes and compound heterozygotes.
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The −50 (G>A) (HBB: c.-100G>A) mutation was first reported as a β-thalassemia (β-thal) allele in a Chinese family. However, the hematological features of carriers with this variant are not available. In this study, we present the hematological data associated with −50 (G>A) to determine its phenotype. During a 4-year period, eight simple heterozygotes and three double heterozygotes for the −50 mutation and α-thalassemia (α-thal) were included. The simple heterozygotes had normal hematological parameters. The double heterozygotes had the hematological findings of simple α-thal heterozygotes. Two subjects with a compound heterozygosity for −50 and β-thal were also found, and both had typical hematological parameters of β-thal trait. Therefore, we present evidence that −50 (G>A) is likely a silent β-thal allele. Compound heterozygotes for −50/β-thal had no phenotype of severe β-thal. This information might be helpful in genetic counseling for couples in thalassemia high-prevalence areas.
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Abstract Objective Mutations of the gap junction beta 2 (GJB2) gene coding for the protein connexin 26 account for up to 50% of nonsyndromic sensorineural hearing loss (NSHL), with specific mutations associated with distinct ethnic groups. A biracial family with nonsyndromic sensorineural deafness consistent with autosomal recessive inheritance was examined for connexin 26 (Cx26) mutations. Study Design Prospective observational study. Methods A family consisting of a Caucasian mother and a Chinese father with two of six children affected by NSHL was examined for Cx26 mutations. Peripheral blood lymphocyte DNA was used to amplify by polymerase chain reaction the Cx26 coding region, followed by mutation detection enhancement gel screening and complete sequencing. Phenotypic characterization using audiometric testing was completed for all children and both parents. Results The two affected children were found to be compound heterozygotes for Cx26 mutations, displaying a previously unreported combination of 35delG and 235delC. The parents were each unaffected heterozygotes consistent with their ethnic heritage, specifically, the Caucasian mother a 35delG heterozygote and the Chinese father a 235delC heterozygote. Conclusions Connexin 26 mutations account for a significant proportion of NSHL worldwide, with specific mutations linked to distinct ethnic groups. Genetic analysis of a biracial family with NSHL revealed a novel 35delG/235delC compound heterozygous state in phenotypically affected children. These results highlight the usefulness of Cx26 mutation screening for genetic counseling and suggest that the 235delC mutation is present in China as it is in Japan and Korea.
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Objective:To perform prenatal diagnosis in a pregnancy with a fetus at-risk for SEA HPFH deletion and β-thalassemia.Methods:PCR-reverse dot blot and long-range PCR methods were used to determine the genotype in the at-risk fetus.Results:The father was revealed to be a heterozygote for the codons 41-42(-TTCT) mutation,the mother a heterozygote for SEA HPFH deletion and the fetus a heterozygote for the codons 41-42(-TTCT) mutation.Conclusions:For pregnant women whose fetuses are at-risk for a compound heterozygote of SEA HPFH deletion and β-thalassemia,prenatal diagnosis should be done.
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Heterozygote advantage
Transferrin saturation
Hereditary hemochromatosis
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Objective:To examine clinical characteristics of heterozygote and double heterozygote of three rare mutations [Hb Constants Spring(Hb CS),Hb Westmead(Hb WS) and Hb Quong Sze(Hb QS)] among alpha-thalassemia patients in Guangxi province, China. Methods:135 alpha-thalassemia patients, and 40 controls, were included in this study. Routine examination of blood and hemoglobin electrophoresis were performed. The alpha-thalassemia mutations were detected using Gap-PCR and reverse dot-blotting. Results: There were no clinical symptoms in three heterozygote groups and the double heterozygote group of αCSα/αWSα. MCV and MCH in the heterozygote group of Hb QS were significantly lower than those in other heterozygote groups(Hb CS and Hb WS)(P0.05). However,there was mild clinical symptoms in the double heterozygote group of αCSα/αQSα, while MCV and MCH were also significantly lower than those in other heterozygote groups(Hb CS and Hb WS)(P 0.05). Conclusions: The heterozygote Hb CS,heterozygote Hb WS and double heterozygote αCSα/αWSα are the silent carrier in clinical manifestations, the heterozygote Hb QS is the thalassemia trait, and the double heterozygote αCSα/αQSα is similar to the HbH disease. It is important to note this variability of clinical manifestations of those double heterozygotes in genetic consultation.
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