Identification of a novel KCNT2 variant in a family with developmental and epileptic encephalopathies: a case report and literature review.

Background: Developmental and epileptic encephalopathies (DEEs) are a group of heterogeneous neurodevelopmental diseases characterized mainly by developmental delay/intellectual disability and early-onset epilepsy. Researchers have identified variations in the KCNT2 gene (OMIM* 610044) as the cause of DEE type 57 (MIM# 617771). Case presentation: We report in this study a 46-year-old woman who presented with early-onset epilepsy, intellectual disability, hypertrichosis, coarse facial features, and short stature. Besides, there were four other affected individuals in her family history, including two elder brothers, a younger brother, and their mother. We collected blood samples from the proband, her two affected brothers, and her clinically normal daughter for genetic analysis. Clinical exome sequencing revealed a novel heterozygous variant in the KCNT2 gene (NM_198503: c.188G>A, p.Arg63His) in the proband and her two affected brothers, while her daughter did not carry this variant. Furthermore, we reviewed all 25 patients identified in the literature with KCNT2 variants and compared their phenotypes. Conclusion: Epilepsy and intellectual disability/developmental delay occur in almost all patients with KCNT2 variants. KCNT2-relevant DEEs partially overlap with the clinical phenotypes of KATP channel diseases, particularly in hypertrichosis and distinctive coarse facial features.

Maternal uniparental disomy for chromosome 6 in 2 prenatal cases with IUGR: case report and literature review.

BACKGROUND: Uniparental disomy (UPD) is a rare genetic condition leading to potential disease risks. Maternal UPD of chromosome 6 upd(6)mat is exceptionally rare, with limited cases reported. This study reported two new cases of upd(6)mat and reviewed the literature of previous cases. CASE PRESENTATION: Both cases exhibited intrauterine growth restriction (IUGR), and genetic analysis confirmed upd(6)mat in each case. The literature review identified a total of 19 cases. IUGR and preterm labor were the most common two symptoms observed, and additional anomalies and genetic variations were also reported in some cases. CONCLUSION: upd(6)mat is potentially associatied with IUGR, but the precise genotype-phenotype relationship remains unclear. The cases with upd(6)mat may present clinical features due to imprinting disorders.

The clinical, myopathological, and genetic analysis of 155 Chinese mitochondrial ophthalmoplegia patients with mitochondrial DNA single large deletions.

BACKGROUND: Progressive external ophthalmoplegia (PEO) is a common subtype of mitochondrial encephalomyopathy. OBJECTIVE: The study aimed to investigate the relationship between mitochondrial DNA (mtDNA) abnormalities, muscle pathology, and clinical manifestations in Chinese patients with single large-scale mtDNA deletion presenting with PEO. METHODS: This is a retrospective single-center study. Patients with PEO who had a single large deletion in mitochondrial DNA were included in this study. The associations were analyzed between mtDNA deletion patterns, myopathological changes, and clinical characteristics. RESULTS: In total, 155 patients with mitochondrial PEO carrying single large-scale mtDNA mutations were enrolled, including 137 chronic progressive external ophthalmoplegia (CPEO) and 18 Kearns-Sayre syndrome (KSS) patients. The onset ages were 9.61 ± 4.12 in KSS and 20.15 ± 9.06 in CPEO. The mtDNA deletions ranged from 2225 bp to 9131 bp, with m.8470_13446del being the most common. The KSS group showed longer deletions than the CPEO group (p = 0.004). Additionally, a higher number of deleted genes encoding respiratory chain complex subunits (p = 0.001) and tRNA genes (p = 0.009) were also observed in the KSS group. A weak negative correlation between the mtDNA deletion size and ages of onset (p < 0.001, r = -0.369) was observed. The proportion of ragged red fibers, ragged blue fibers, and cytochrome c negative fibers did not correlate significantly with onset ages (p > 0.05). However, a higher percentage of abnormal muscle fibers corresponds to an increased prevalence of exercise intolerance, limb muscle weakness, dysphagia, and cerebellar ataxia. CONCLUSION: We reported a large Chinese cohort consisting of mitochondrial PEO patients with single large-scale mtDNA deletions. Our results demonstrated that the length and locations of mtDNA deletions may influence onset ages and clinical phenotypes. The severity of muscle pathology could not only indicate diagnosis but also may be associated with clinical manifestations beyond the extraocular muscles.

Expanding the mutational spectrum of ZTTK syndrome: A de novo variant with global developmental delay and malnutrition in a Chinese patient.

BACKGROUND: Zhu-Tokita-Takenouchi-Kim (ZTTK, OMIM 617140) syndrome is a severe multisystem developmental disorder characterized by intellectual disability, developmental delay, cortical malformations, epilepsy, visual problems, musculoskeletal abnormalities, and congenital malformations. ZTTK syndrome is caused by a heterozygous pathogenic variant of the SON gene (NM_138927) at chromosome 21q22.1. The purpose of this study was to investigate the pathogenesis of a 6-month-old Chinese child who exhibited global developmental delay, muscle weakness, malnutrition, weight loss, and strabismus, brain abnormality, immunological system abnormalities. METHODS: The little girl was tested for medical exome sequencing (MES) and mtDNA sequencing in trio. And, the mutation was validated by Sanger sequencing. RESULTS: A novel de novo frameshift variant, c.1845_1870del26 (p.G616Sfs*61), in the SON gene was found in the proband. CONCLUSION: We described a 6-month-old Chinese child with global developmental delay caused by pathogenic de novo mutation c.1845_1870del26 (p.G616Sfs*61) in the SON. Apart from a founder mutation, we reviewed the phenotypic abnormalities and genotypes in 79 individuals. The data showed that global developmental delay is accompanied by other system disorders. Our findings expanded the mutational spectrum of ZTTK syndrome and provide genetic counseling of baby with global developmental delay.

Prevalence estimation of ATTRv in China based on genetic databases.

Introduction: Amyloid transthyretin (ATTR) is divided into either hereditary (ATTRv) or sporadic (ATTRwt) and ATTRv is a rare hereditary disease transmitted as an autosomal dominant manner. Its global prevalence is traditionally estimated as 5,000 to 10,000 persons. However, it may be underestimated and the exact prevalence of ATTRv in China mainland remains unknown. Methods: The Genome Aggregation database (gnomAD) database (containing 125,748 exomes) and two genomic sequencing databases--China Metabolic Analytics Project (ChinaMAP) (containing 10588 individuals) and Amcarelab gene database (containing 45392 exomes), were integrated to estimate the prevalence of ATTRv in the world and mainland Chinese populations. Pathogenic variants allele frequency and the prevalence of ATTRv was calculated. Results: Six variants, counting 470 alleles, were defined as pathogenic variants in gnomAD. The prevalence of ATTRv in the world population was 57.4/100,000. Two variants (2 allele counts) and 15 variants (34 individuals) were defined as pathogenic variants in the ChinaMAP database and the Amcarelab exome database, respectively. Thus, the estimated prevalence interval of ATTRv in mainland China was 18.9/100,000-74,9/100,000. Conclusion: The present study demonstrated that the previous prevalence was greatly underestimated using traditional methods. Therefore, raising awareness of the disease is essential for recognizing ATTRv in its early stage.

Use of dual genomic sequencing to screen mitochondrial diseases in pediatrics: a retrospective analysis.

Mitochondrial diseases (MDs) were a large group multisystem disorders, attributable in part to the dual genomic control. The advent of massively sequencing has improved diagnostic rates and speed, and was increasingly being used as a first-line diagnostic test. Paediatric patients (aged < 18 years) who underwent dual genomic sequencing were enrolled in this retrospective multicentre study. We evaluated the mitochondrial disease criteria (MDC) and molecular diagnostic yield of dual genomic sequencing. Causative variants were identified in 177 out of 503 (35.2%) patients using dual genomic sequencing. Forty-six patients (9.1%) had mitochondria-related variants, including 25 patients with nuclear DNA (nDNA) variants, 15 with mitochondrial DNA (mtDNA) variants, and six with dual genomic variants (MT-ND6 and POLG; MT-ND5 and RARS2; MT-TL1 and NARS2; MT-CO2 and NDUFS1; MT-CYB and SMARCA2; and CHRNA4 and MT-CO3). Based on the MDC, 15.2% of the patients with mitochondria-related variants were classified as "unlikely to have mitochondrial disorder". Moreover, 4.5% of the patients with non-mitochondria-related variants and 1.43% with negative genetic tests, were classified as "probably having mitochondrial disorder". Dual genomic sequencing in suspected MDs provided a more comprehensive and accurate diagnosis for pediatric patients, especially for patients with dual genomic variants.

Identification of TUBB8 Variants in 5 Primary Infertile Women with Multiple Phenotypes in Oocytes and Early Embryos.

Tubulin beta 8 class VIII (TUBB8) is a ß-tubulin isotype that is specifically expressed in human oocytes and early embryos. It has been identified as a disease-causing gene in primary female infertility by affecting oocyte maturation arrest. This study investigated the genetic cause of female infertility in five patients from four families. Five women with primary infertility were recruited. Medical-exome sequencing and Sanger sequencing were performed on the patients, and their family members to identify candidate genes that explained infertility. Additionally, the morphology of oocytes and zygotes from the patients and controls were assessed. We observed recurrent oocytes MI arrest, oocytes abnormal fertilization, uncleaved embryos, and embryo transfer failure in the patients. Heterozygous missense variants in TUBB8, c.538G > A (p.V180M), c.527C > G (p.S176W), c.124C > G (p.L42V), and c.628A > C (p.I210L), were verified in four unrelated families. This study expanded the mutational spectrum of TUBB8 by identifying three novel heterozygous missense variants. Screening for TUBB8 mutation demonstrated the diagnostic utility of female infertility.

Case report: A novel mutation in TRPS1 identified in a Chinese family with tricho-rhino-phalangeal syndrome I: A therapeutic challenge.

Tricho-rhino-phalangeal syndrome (TRPS) is a rare autosomal dominant malformation caused by mutations involving the TRPS1 gene. Patients with TRPS exhibit distinctive craniofacial and skeletal abnormalities. This report presents three intra-familial cases with TRPS1 gene mutations that showed the characteristic features of TRPS. A 13-year-old boy was admitted to Department of Endocrinology for the evaluation of short stature. Physical examination revealed that the boy had thin sparse hair, pear-shaped nose, protruding ears, small jaw and brachydactyly. A survey of his family history indicated that the boy's sister and mother shared the same clinical features. Radiological techniques demonstrated a different degree of skeletal abnormalities in these siblings. Next-generation sequencing and quantitative PCR were performed and showed a novel deletion mutation in exons 3-5 in the three familial cases, confirming the diagnosis of TRPS I. The healthy father did not carry the deletion mutation. Currently, there was no specific therapy for TRPS I; however, genetic consultation may be useful for family planning.

Clinical Utility of Medical Exome Sequencing: Expanded Carrier Screening for Patients Seeking Assisted Reproductive Technology in China.

Purpose: Expanded carrier screening (ECS) is an effective method to identify at-risk couples (ARCs) and avoid birth defects. This study aimed to reveal the carrier spectrum in the Chinese population and to delineate an expanded carrier gene panel suitable in China. Methods: Medical exome sequencing (MES), including 4,158 disease-causing genes, was offered to couples at two reproductive centers. It was initially used as a diagnostic yield for potential patients and then used for ECS. Clinical information and ECS results were retrospectively collected. Results: A total of 2,234 couples, representing 4,468 individuals, underwent MES. In total, 254 individuals showed genetic disease symptoms, and 56 of them were diagnosed with genetic diseases by MES. Overall, 94.5% of them were carriers of at least one disease-causing variant. The most prevalent genes were GJB2 for autosomal recessive disorders and G6PD for X-linked diseases. The ARC rate was 9.80%, and couples were inclined to undergo preimplantation genetic testing when diseases were classified as "profound" or "severe." Conclusion: This study provided insight to establish a suitable ECS gene panel for the Chinese population. Disease severity significantly influenced reproductive decision-making. The results highlighted the importance of conducting ECS for couples before undergoing assisted reproductive technology.

Multisystem Mitochondrial Disease Associated With a Mare m.10000G>A Mitochondrial tRNA Gly (MT-TG) Variant.

Background: Mitochondrial diseases are clinically heterogeneous, can occur at any age, and can manifest with a wide range of clinical symptoms. They can involve any organ or tissue, characteristically involve multiple systems, typically affecting organs that are highly dependent on aerobic metabolism, and making a definitive molecular diagnosis of a mitochondrial disorder is challenging. Methods: Clinical data of the proband and his family members were gathered in a retrospective study. Whole-exome sequencing and full-length sequencing of the mitochondrial genome that were performed on peripheral blood, urine, and oral mucosa cells were applied for genetic analysis. Results: In this study, we reported a childhood-onset mitochondrial phenotype in a 13-year-old patient. Analysis of the next-generation sequencing data of the nuclear genome and the full-length sequencing of the mitochondrial genome revealed the rare m.10000G>A variant in MT-TG that was present at variable heteroplasmy levels across tissue types: 32.7% in the blood, 56.15% in urinary epithelial cells, and 27.3% in oral mucosa cells. No variant was found in the peripheral blood of his mother and sister. No pathogenic mutation of nDNA was found. Conclusion: Our results added evidence that the de novo m.10000G>A variation in the highly conserved sequence of MT-TG appears to suggest a childhood-onset mitochondrial phenotype in the 13-year-old patient, thus broadening the genotypic interpretation of mitochondrial DNA-related diseases.

Case Report: Report of Two Cases of Interstitial Lung Disease Caused by Novel Compound Heterozygous Variants in the ABCA3 Gene.

Interstitial lung disease (ILD) is a heterogeneous group of pulmonary disorders involving the lung interstitium and distal airways, also known as diffuse lung disease. The genetic defects resulting in alveolar surfactant protein dysfunction are a rare cause of ILD in pediatric patients. We report two unrelated pediatric patients with shortness of breath, dyspnea and hypoxemia, and the chest CT findings including patchy ground-glass opacity in both lung fields, suggestive of diffuse ILD. One patient was a full-term male infant who had shortness of breath a few hours after the birth, and then developed into severe respiratory distress syndrome (RDS). Whole exome sequencing revealed novel compound heterozygous variants in the ABCA3 gene (NM_001,089.3): paternally inherited c.4035+5G > A and c.668T > C (p.M223T), and maternally inherited c.1285+4A > C. The second patient was a 34-month-old boy with onset of chronic repeated cough and hypoxemia at 9 months of age. We unveiled novel compound heterozygous ABCA3 variants (c.704T > C, p.F235S; c.4037_4040del, p.T1346Nfs*15) in this patient. Surfactant protein dysfunction due to bi-allelic mutations in the ABCA3 gene was the cause of ILD in two patients. The novel mutations found in this study expanded the spectrum of known mutations in the ABCA3 gene.

Case Report: Be Aware of "New" Features of Niemann-Pick Disease: Insights From Two Pediatric Cases.

Niemann-Pick disease is a relatively common lysosomal storage disease. Cholestatic liver disease is a typical clinical phenotype of Niemann-Pick disease in infancy. The diagnosis is traditionally based on Niemann-Pick cells in bone marrow smears or liver biopsies. Treatment for cholestatic liver disease mainly includes ursodeoxycholic acid and liver protection drugs. Here, we reported two cases of Niemann-Pick disease type C, diagnosed by genetic analysis during early infancy. Besides cholestatic jaundice, the two patients also exhibited signs of immune system hyperactivity, such as elevated immunoglobulins or multiple autoantibodies, which might require the application of glucocorticoids. In addition, three novel missense variants of the NPC1 gene were identified. The findings suggest that immune activation should be considered as a "new" clinical phenotype of lysosomal storage diseases.

Expanding the mutational spectrum of Rahman syndrome: A rare disorder with severe intellectual disability and particular facial features in two Chinese patients.

BACKGROUND: The study aimed to investigate the clinical and genetic features of Rahman syndrome caused by HIST1H1E gene mutations. METHODS: We retrospectively analyzed the clinical information and genetic testing results of a Rahman syndrome family in an outpatient clinic in August 2020 and summarized the clinical characteristics of the HIST1H1E gene mutations in conjunction with peer-reviewed reports. RESULTS: A 4-year-old boy was diagnosed with severe developmental delay and with specific features (large head, full cheeks, high hairline, low-set ear, sparse eyebrows, and short neck) similar to his mother (mild intellectual disability, high hairline, reduced hair, ptosis, sagging skin, and hyperkeratosis) and premature aging. Trio whole exome sequencing (WES) revealed a novel maternal c.368dup (p.G124Rfs*72) heterozygous mutation in the HIST1H1E gene. There have been only a few reported cases with mainly de novo mutations. Only six peer-reviewed articles in English and one in Chinese have been published regarding this syndrome. From 48 children with Rahman syndrome, 21 were males and 27 were females encompassing 25 mutations in the HIST1H1E gene. All mutations located in C-terminal tail were frameshift mutations leading to premature protein termination. CONCLUSION: Rahman syndrome, caused by the HIST1H1E gene mutation, is a rare autosomal dominant disorder in which the patient has an unusual facial appearance with high hairline and full cheeks, and clinical manifestations of mild to severe intellectual disability, motor delay and speech delay. Genetic testing may assist in the diagnosis of these patients. This diagnosis will permit early speech rehabilitation to improve their quality of life.

Accurate Identification of Breakpoints in a Cryptic Reciprocal Translocation by Whole-Genome Sequencing.

Chromosomal abnormalities are a common cause of spontaneous abortions, but conventional detection methods (karyotype, FISH, and chromosomal microarray [CMA]) have limitations, and many cryptic balanced chromosomal rearrangements are difficult to detect. We describe a couple who experienced a missed abortion, studied by CMA. CMA of the abortion tissue detected a 1.62-Mb duplication at 14q11.2 and a 5.09-Mb deletion at 21q11.2q21.1, while the couple seemed to have a normal karyotype. Combining the results of CMA, whole-genome sequencing (WGS) breakpoint analysis, Sanger sequencing, and FISH, we found that the father was a 46,XY,t(14;21)(q11.2;q21.1) balanced translocation carrier. Our results indicate that WGS is an efficient and accurate approach to map breakpoints of cryptic reciprocal balanced translocations undetectable by standard karyotype.

Identification and Functional Characterization of a Novel Nonsense Variant in ARR3 in a Southern Chinese Family With High Myopia.

ARR3 has been associated with X-linked, female-limited, high myopia. However, using exome sequencing (ES), we identified the first high myopia case with hemizygous ARR3-related mutation in a male patient in a Southern Chinese family. This novel truncated mutation (ARR3: c.569C>G, p.S190*) co-segregated with the disease phenotype in affected family members and demonstrated that high myopia caused by ARR3 is not X-linked, female-limited, where a complicated X-linked inheritance pattern may exist. Thus, our case expanded the variant spectrum in ARR3 and provided additional information for genetic counseling, prenatal testing, and diagnosis. Moreover, we characterized the nonsense-mediated decay of the ARR3 mutant mRNA and discussed the possible underlying pathogenic mechanisms.

Kv3.1 channelopathy: a novel loss-of-function variant and the mechanistic basis of its clinical phenotypes.

BACKGROUND: KCNC1 encodes Kv3.1, a subunit of the Kv3 voltage-gated potassium channels. It is predominantly expressed in inhibitory GABAergic interneurons and cerebellar neurons. Kv3.1 channelopathy has been linked to a variety of human diseases including epilepsy, developmental delay, and ataxia. Characterization of structural and functional disturbances of this channel, and its relationship to a heterogenous group of clinical phenotypes, is a current topic of research. We herein characterize the clinical phenotype as well as the functional and structural consequences of the novel KCNC1 p.R317S variant. We further set out to explore the mechanistic basis for the spectrum of KCNC1 related channelopathies. METHODS: Variant was identified via whole-exome sequencing and its functional impact was determined using two-electrode voltage clamp recordings in Xenopus laevis oocytes. Homolog modeling and in silico structural analysis were performed on the p.R317S variant and other KCNC1 related variants. RESULTS: We identified a novel loss-of-function KCNC1 variant c.949C>A (p.R317S) presenting with symptoms similar to myoclonic epilepsy and ataxia due to potassium channel (MEAK), but with distinct radiological features. Functional analysis in the Xenopus laevis oocyte's expression system revealed that the current amplitudes were significantly decreased in the p.R317S variant compared to the wild type, indicating a dominant-negative effect. Atomic structural analysis of the KCNC1 related variants provided a possible mechanistic explanation for the heterogeneity in the clinical spectrum. CONCLUSIONS: We have identified the p.R317S loss-of-function variant in the KCNC1 gene, expanded the spectrum of potassium channelopathy and provided mechanistic insights into KCNC1 related disorders.

Missense mutation in DYNC1H1 gene caused psychomotor developmental delay and muscle weakness: A case report.

BACKGROUND: The DYNC1H1 gene encodes a part of the dynamic protein, and the protein mutations may further affect the growth and development of neurons, resulting in degeneration of anterior horn cells of the spinal cord, and a variety of clinical phenotypes finally resulting in axonal Charcot-Marie-Tooth disease type 20 (CMT20), mental retardation 13 (MRD13) and spinal muscular atrophy with lower extremity predominant 1 (SMA-LED). The incidence of the disease is low, and it is difficult to diagnose, especially in children. Here, we report a case of DYNC1H1 gene mutation and review the related literature to improve the pediatrician's understanding of DYNC1H1 gene-related disease to make an early correct diagnosis and provide better services for children. CASE SUMMARY: A 4-mo-old Chinese female child with adducted thumbs, high arch feet, and epileptic seizure presented slow response, delayed development, and low limb muscle strength. Electroencephalogram showed abnormal waves, a large number of multifocal sharp waves, sharp slow waves, and multiple spasms with a series of attacks. High-throughput sequencing and Sanger sequencing identified a heterozygous mutation, c.5885G>A (p.R1962H), in the DYNC1H1 gene (NM_001376) of the proband, which was not identified in her parents. Combined with the clinical manifestations and pedigree of this family, this mutation is likely pathogenic based on the American Academy of Medical Genetics and Genomics guidelines. The child was followed when she was 1 year and 2 mo old. The magnetic resonance imaging result was consistent with the findings of white matter myelinated dysplasia and congenital giant gyrus. The extensive neurogenic damage to the extremities was considered, as the results of electromyography showed that the motor conduction velocity and sensory conduction of the nerves of the extremities were not abnormal, and the degree of fit of the children with severe contraction was poor. At present, the child is 80 cm in length and 9 kg in weight, with slender limbs and low muscle strength, and still does not raise her head. She cannot sit or speak. Speech, motor, and mental development was significantly delayed. There is still no effective treatment for this disease. CONCLUSION: We herein report a de novo variant of DYNC1H1 gene, c.5885G>A (p.R1962H), leading to overlapping phenotypes (seizure, general growth retardation, and muscle weakness) of CMT20, MRD13, and SMA-LED, but there is no effective treatment for such condition. Our case enriches the DYNC1H1 gene mutation spectrum and provides an important basis for clinical diagnosis and treatment and genetic counseling.

Exome-based preconception carrier testing for consanguineous couples in China.

OBJECTIVE: To evaluate the utility of clinical exome sequencing (ES)-based carrier screening in Chinese consanguineous couples. METHODS: Consanguineous couples were screened for autosomal recessive (AR) disorders using the clinical ES of 5000 genes associated with human diseases. RESULTS: We recruited 14 couples who elected to have sequencing. One couple was related as first cousins and 13 as second cousins. Both partners carrying the same pathogenic variant were detected in four couples. One couple was found in which one partner carried a splice variant, and the other had a missence variant of the same gene. These five couples were identified as being at risk of having a child affected by an AR disorder. CONCLUSION: Our study demonstrates that ES-based preconception screening yields a clinical value for Chinese consanguineous couples. It enables to detect at-risk couples for rare AR diseases.

Clinical Utility of Rapid Exome Sequencing Combined With Mitochondrial DNA Sequencing in Critically Ill Pediatric Patients With Suspected Genetic Disorders.

Genetic disorders are a frequent cause of hospitalization, morbidity and mortality in pediatric patients, especially in the neonatal or pediatric intensive care unit (NICU/PICU). In recent years, rapid genome-wide sequencing (exome or whole genome sequencing) has been applied in the NICU/PICU. However, mtDNA sequencing is not routinely available in rapid genetic diagnosis programs, which may fail to diagnose mtDNA mutation-associated diseases. Herein, we explored the clinical utility of rapid exome sequencing combined with mtDNA sequencing in critically ill pediatric patients with suspected genetic disorders. Rapid clinical exome sequencing (CES) was performed as a first-tier test in 40 critically ill pediatric patients (aged from 6 days to 15 years) with suspected genetic conditions. Blood samples were also collected from the parents for trio analysis. Twenty-six patients presented with neuromuscular abnormalities or other systemic abnormalities, suggestive of suspected mitochondrial diseases or the necessity for a differential diagnosis of other diseases, underwent rapid mtDNA sequencing concurrently. A diagnosis was made in 18 patients (45.0%, 18/40); three cases with de novo autosomal dominant variants, ten cases with homozygous or compound heterozygous variants, three cases with hemizygous variants inherited from mother, three cases with heterozygous variants inherited from either parent, and one case with a mtDNA mutation. The 18 patients were diagnosed with metabolic (n = 7), immunodeficiency (n = 4), cardiovascular (n = 2), neuromuscular (n = 2) disorders, and others. Genetic testing reports were generated with a median time of 5 days (range, 3-9 days). Thirteen patients that were diagnosed had an available medical treatment and resulted in a positive outcome. We propose that rapid exome sequencing combined with mitochondrial DNA sequencing should be available to patients with suspected mitochondrial diseases or undefined clinical features necessary for making a differential diagnosis of other diseases.

Novel Mutations in the GTPBP3 Gene for Mitochondrial Disease and Characteristics of Related Phenotypic Spectrum: The First Three Cases From China.

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.