Biparental Inheritance of Mitochondrial DNA in Humans Luo, Shiyu; Valencia, C. Alexander; Zhang, Jinglan ...
Proceedings of the National Academy of Sciences - PNAS,
12/2018, Volume:
115, Issue:
51
Journal Article
Peer reviewed
Open access
Although there has been considerable debate about whether paternal mitochondrial DNA (mtDNA) transmission may coexist with maternal transmission of mtDNA, it is generally believed that mitochondria ...and mtDNA are exclusively maternally inherited in humans. Here, we identified three unrelated multigeneration families with a high level of mtDNA heteroplasmy (ranging from 24 to 76%) in a total of 17 individuals. Heteroplasmy of mtDNA was independently examined by high-depth whole mtDNA sequencing analysis in our research laboratory and in two Clinical Laboratory Improvement Amendments and College of American Pathologists-accredited laboratories using multiple approaches. A comprehensive exploration of mtDNA segregation in these families shows biparental mtDNA transmission with an autosomal dominantlike inheritance mode. Our results suggest that, although the central dogma of maternal inheritance of mtDNA remains valid, there are some exceptional cases where paternal mtDNA could be passed to the offspring. Elucidating the molecular mechanism for this unusual mode of inheritance will provide new insights into how mtDNA is passed on from parent to offspring and may even lead to the development of new avenues for the therapeutic treatment for pathogenic mtDNA transmission.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Identification of variants in the acid α‐glucosidase (GAA) gene in Pompe disease provides valuable insights and systematic overviews are needed. We report on the number, nature, frequency, and ...geographic distribution of GAA sequence variants listed in the Pompe Registry, a long‐term, observational program and the largest global repository of Pompe disease data. Variant information was reviewed and compared with publicly available GAA databases/resources. Among 1,079 eligible patients, 2,075 GAA variants (80 unique novel) were reported. Variants were listed by groups representing Pompe disease phenotypes. Patients were classified as Group A: Symptom onset ≤ 12 months of age with cardiomyopathy; Group B: Symptom onset ≤ 12 years of age (includes patients with symptom onset ≤ 12 months of age without cardiomyopathy); or Group C: Symptom onset > 12 years of age. Likely impact of novel variants was predicted using bioinformatics algorithms. Variants were classified by pathogenicity using ACMG guidelines. Data reported from the Pompe Registry provide new information about the distribution of GAA variants globally and across the clinical spectrum, add to the number and diversity of GAA variants registered in public databases through published data sharing, provide a first indication of the severity of novel variants, and assist in diagnostic practice and outcome prediction.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Mucopolysaccharidosis IVA (MPS IVA, Morquio A syndrome) is a rare autosomal recessive lysosomal storage disorder caused by mutations in the N‐acetylgalactosamine‐6‐sulfatase (GALNS) gene. We ...collected, analyzed, and uniformly summarized all published GALNS gene variants, thus updating the previous mutation review (published in 2014). In addition, new variants were communicated by seven reference laboratories in Europe, the Middle East, Latin America, Asia, and the United States. All data were analyzed to determine common alleles, geographic distribution, level of homozygosity, and genotype‐phenotype correlation. Moreover, variants were classified according to their pathogenicity as suggested by ACMG. Including those previously published, we assembled 446 unique variants, among which 68 were novel, from 1190 subjects (including newborn screening positive subjects). Variants' distribution was missense (65.0%), followed by nonsense (8.1%), splicing (7.2%), small frameshift deletions(del)/insertions(ins) (7.0%), intronic (4.0%), and large del/ins and complex rearrangements (3.8%). Half (50.4%) of the subjects were homozygous, 37.1% were compound heterozygous, and 10.7% had only one variant detected. The novel variants underwent in silico analysis to evaluate their pathogenicity. All variants were submitted to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) to make them publicly available. Mutation updates are essential for the correct molecular diagnoses, genetic counseling, prenatal and preimplantation diagnosis, and disease management.
In this mutation update, we collected, analyzed, classified and uniformly summarized all published GALNS gene variants. In addition, 68 new variants were communicated by seven reference laboratories in Europe, the Middle East, Latin America, Asia, and the United States.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
While next-generation sequencing (NGS) has transformed genetic testing, it generates large quantities of noisy data that require a significant amount of bioinformatics to generate useful ...interpretation. The accuracy of variant calling is therefore critical. Although GATK HaplotypeCaller is a widely used tool for this purpose, newer methods such as DeepVariant have shown higher accuracy in assessments of gold-standard samples for whole-genome sequencing (WGS) and whole-exome sequencing (WES), but a side-by-side comparison on clinical samples has not been performed. Trio WES was used to compare GATK (4.1.2.0) HaplotypeCaller and DeepVariant (v0.8.0). The performance of the two pipelines was evaluated according to the Mendelian error rate, transition-to-transversion (Ti/Tv) ratio, concordance rate, and pathological variant detection rate. Data from 80 trios were analyzed. The Mendelian error rate of the 77 biological trios calculated from the data by DeepVariant (3.09 ± 0.83%) was lower than that calculated from the data by GATK (5.25 ± 0.91%) (p < 0.001). DeepVariant also yielded a higher Ti/Tv ratio (2.38 ± 0.02) than GATK (2.04 ± 0.07) (p < 0.001), suggesting that DeepVariant proportionally called more true positives. The concordance rate between the 2 pipelines was 88.73%. Sixty-three disease-causing variants were detected in the 80 trios. Among them, DeepVariant detected 62 variants, and GATK detected 61 variants. The one variant called by DeepVariant but not GATK HaplotypeCaller might have been missed by GATK HaplotypeCaller due to low coverage. OTC exon 2 (139 bp) deletion was not detected by either method. Mendelian error rate calculation is an effective way to evaluate variant callers. By this method, DeepVariant outperformed GATK, while the two pipelines performed equally in other parameters.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
To demonstrate the feasibility of presymptomatic diagnosis of spinal muscular atrophy (SMA) through newborn screening (NBS).
We performed a screening trial to assess all newborns who underwent ...routine newborn metabolic screening at the National Taiwan University Hospital newborn screening center between November 2014 and September 2016. A real-time polymerase chain reaction (RT-PCR) genotyping assay for the SMN1/SMN2 intron 7 c.888+100A/G polymorphism was performed to detect homozygous SMN1 deletion using dried blood spot (DBS) samples. Then the exon 7 c.840C>T mutation and SMN2 copy number were determined by both droplet digital PCR (ddPCR) using the original screening DBS and multiplex ligation-dependent probe amplification (MLPA) using a whole blood sample.
Of the 120 267 newborns, 15 tested positive according to the RT-PCR assay. The DBS ddPCR assay excluded 8 false-positives, and the other 7 patients were confirmed by the MLPA assay. Inclusion of the second-tier DBS ddPCR screening assay resulted in a positive prediction value of 100%. The incidence of SMA was 1 in 17 181 (95% CI, 1 in 8323 to 1 in 35 468). Two of the 3 patients with 2 copies of SMN2 and all 4 patients with 3 or 4 copies of SMN2 were asymptomatic at the time of diagnosis. Five of the 8 false-positives were caused by intragenic recombination between SMN1 and SMN2.
Newborn screening can detect patients affected by SMA before symptom onset and enable early therapeutic intervention. A combination of a RT-PCR and a second-tier ddPCR can accurately diagnose SMA from DBS samples with no false-positives.
ClinicalTrials.gov NCT02123186.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Aromatic l‐amino acid decarboxylase deficiency (AADCD) is a rare inherited disease prevalent in South East Asia. This disease is due to the founder mutation IVS 6 + 4A > T (c.714 + 4A > T), which ...accounts for most alleles. Patients with this mutation have severe phenotypes. About 90 % of these patients in South East Asia do not have head control and cannot sit, stand, or speak from birth to the time of observation. In 2012, a gene study to treat these patients with intraputamen injection of adeno‐associated virus2‐human AADC showed prominent motor improvement and an increased PDMS‐2 score 12 months after treatment. In addition, systemic gene therapy in a mouse model of AADCD achieved widespread correction of the Ddc gene. In this article, we review the natural history, clinical course, and treatment effects seen in these clinical and mouse studies. Future studies focusing on noninvasive viral vector delivery or alternative emerging treatments may also benefit patients with AADCD.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The SARS‐CoV‐2 pandemic challenges healthcare systems worldwide. Within inherited metabolic disorders (IMDs) the vulnerable subgroup of intoxication‐type IMDs such as organic acidurias (OA) and urea ...cycle disorders (UCD) show risk for infection‐induced morbidity and mortality. This study (observation period February 2020 to December 2021) evaluates impact on medical health care as well as disease course and outcome of SARS‐CoV‐2 infections in patients with intoxication‐type IMDs managed by participants of the European Registry and Network for intoxication type metabolic diseases Consortium (E‐IMD). Survey's respondents managing 792 patients (n = 479 pediatric; n = 313 adult) with intoxication‐type IMDs (n = 454 OA; n = 338 UCD) in 14 countries reported on 59 (OA: n = 36; UCD: n = 23), SARS‐CoV‐2 infections (7.4%). Medical services were increasingly requested (95%), mostly alleviated by remote technologies (86%). Problems with medical supply were scarce (5%). Regular follow‐up visits were reduced in 41% (range 10%–50%). Most infected individuals (49/59; 83%) showed mild clinical symptoms, while 10 patients (17%; n = 6 OA including four transplanted MMA patients; n = 4 UCD) were hospitalized (metabolic decompensation in 30%). ICU treatment was not reported. Hospitalization rate did not differ for diagnosis or age group (p = 0.778). Survival rate was 100%. Full recovery was reported for 100% in outpatient care and 90% of hospitalized individuals. SARS‐CoV‐2 impacts health care of individuals with intoxication‐type IMDs worldwide. Most infected individuals, however, showed mild symptoms and did not require hospitalization. SARS‐CoV‐2‐induced metabolic decompensations were usually mild without increased risk for ICU treatment. Overall prognosis of infected individuals is very promising and IMD‐specific or COVID‐19‐related complications have not been observed.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Objective
Children with aromatic l‐amino acid decarboxylase (AADC) deficiency suffer from severe motor dysfunction. Restoration of dopamine levels in the putamen by gene therapy has led to ...significant improvement in motor function. This study explored brain structure changes in patients.
Methods
Brain diffusion tensor imaging (DTI) was performed before and 12 months after gene therapy. Whole‐brain tract‐specific analysis was performed to assess white matter microstructural integrity.
Results
In the 8 patients (aged 1.67–8.42 years) enrolled in the study, gene therapy did not affect macroscopic structure. DTI before gene therapy revealed lower total mean fractional anisotropy (FA) values in patients than in the age‐matched pretreatment controls (p = 0.017; median difference = −0.0136; 95% confidence interval CI −0.0319, −0.0126). After gene therapy, total mean FA increased (p = 0.012, median difference = 0.0211, 95% CI 0.0094, 0.0456), and the values in the patients were not different from the age‐matched posttreatment controls. Increase in total mean FA after gene therapy in patients was correlated with their increase in motor score (r = 0.846; p = 0.008), but was inversely correlated with their ages at the time of gene therapy (r = −0.754; p = 0.031). Corticospinal tracts, and the thalamic radiation and callosal fibers involving motor function, improved after gene therapy.
Interpretation
Improvement in the microstructural integrity of white matter tracts is associated with the improvement in motor function following gene therapy. Ann Neurol 2019;85:644–652
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
9.
The modern face of newborn screening Chien, Yin-Hsiu; Hwu, Wuh-Liang
Pediatrics and neonatology,
February 2023, 2023-02-00, 2023-02-01, Volume:
64
Journal Article
Peer reviewed
Open access
Newborn screening (NBS) has been developed for years to identify newborns with severe but treatable conditions. Taiwan's NBS system, after the initial setup for a total coverage of newborns in 1990s, ...was later optimized to ensure the timely return of results in infants with abnormal results. Advancements in techniques such as Tandem mass spectrometry enable the screening into a multiplex format and increase the conditions to be screened. Furthermore, advances in therapies, such as enzyme replacement therapy, stem cell transplantation, and gene therapy, significantly expand the needs for newborn screening. Advances in genomics and biomarkers discovery improve the test accuracy with the assistance of second-tier tests, and have the potential to be the first-tier test in the future. Therefore, challenge of NBS now is the knowledge gap, including the evidence of the long-term clinical benefits in large cohorts especially in conditions with new therapies, phenotypic variations and the corresponding management of some screened diseases, and cost-effectiveness of extended NBS programs. A short-term and a long-term follow-up program should be implemented to gather those outcomes better especially in the genomic era. Ethical and psychosocial issues are also potentially encountered frequently. Essential education and better informed consent should be considered fundamental to parallel those new tests into future NBS.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
Pompe disease is one of the few neuromuscular diseases with an approved drug therapy, which has been available since 2006. Our study aimed to determine the real-world long-term efficacy ...and safety of alglucosidase alfa.
Methods
This multicenter retrospective study (NCT02824068) collected data from adult Pompe disease patients receiving ERT for at least 3 years. Demographics and baseline characteristics, muscle strength, lung function (FVC), walking capability (6MWT), and safety were assessed once a year. Evaluation was done on the group and individual levels, using quantitative linear models (
t
test) and general univariate linear models (ANOVA).
Findings
Sixty-eight adult Pompe disease patients from four countries (Spain, Taiwan, Italy, Germany (STIG)) participated. The mean follow-up was 7.03 years ± 2.98. At group level in all outcome measures, an initial improvement followed by a secondary decline was observed. After 10 years, the 6MWT
%pred
showed the most sustained positive effect (
p
= 0.304). The MRC
%max
remained stable with a mild decline (
p
= 0.131), however, FVC
%pred
deteriorated significantly (
p
< 0.001) by 14.93% over 10 years of ERT. The progression rate of FVC
%pred
under ERT could be explained in most of the patients (83.5%) by the disease severity at baseline. Furthermore, our study shows a decline in the FVC combined with an increase in non-invasive and invasive ventilation requirements in adult Pompe disease patients over time.
Conclusions
The STIG real-world study confirms an initial efficacy of ERT in the first years with a secondary sustained decline in multiple outcome measures. Further efforts are required to establish a more valid long-term monitoring and improved therapies.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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