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Background: Newborn screening (NBS), such as tandem mass spectrometry (MS/MS), may yield false positive/negative results. Next-generation sequencing (NGS) has the potential to provide increased data output, efficiencies, and applications. This study aimed to analyze the types and distribution of pathogenic gene mutations in newborns in Huzhou, Zhejiang province, China and explore the applicability of NGS and MS/MS in NBS. Methods: Blood spot samples from 1263 newborns were collected. NGS was employed to screen for pathogenic variants in 542 disease-causing genes, and detected variants were validated using Sanger sequencing. Simultaneously, 26 inherited metabolic diseases (IMD) were screened using MS/MS. Positive or suspicious samples identified through MS/MS were cross-referenced with the results of NGS. Results: Among all newborns, 328 had no gene mutations detected. NGS revealed at least one gene mutation in 935 newborns, with a mutation rate of 74.0%. The top 5 genes were FLG, GJB2, UGT1A1, USH2A, and DUOX2. According to American College of Medical Genetics guidelines, gene mutations in 260 cases were classified as pathogenic or likely pathogenic mutation, with a positive rate of 20.6%. The top 5 genes were UGT1A1, FLG, GJB2, MEFV, and G6PD. MS/MS identified 18 positive or suspicious samples for IMD and 1245 negative samples. Verification of these cases by NGS results showed no pathogenic mutations, resulting in a false positive rate of 1.4% (18/1263). Conclusion: NBS using NGS technology broadened the range of diseases screened, and enhanced the accuracy of diagnoses in comparison to MS/MS for screening IMD. Combining NGS and biochemical screening would improve the efficiency of current NBS. [ABSTRACT FROM AUTHOR]

Background & Objectives: Charcot-Marie-Tooth (CMT) disease is a group of hereditary sensorimotor neuropathies with a great variability of genotypes and phenotypes. The aims of the study were to provide a general perspective of the clinical manifestations and the frequency of genetic subtypes in CMT patients from a medical center in Taiyuan, northern China. Methods: Twenty-eight unrelated CMT patients were enrolled from a research center in northern China according to the CMT diagnosis criteria formulated by De Jonghe et al. in 1998. Then multiplex ligation-dependent probe amplification (MLPA) testing combined with next-generation sequencing (NGS) were performed among 18 of these patients. Results: PMP22 duplications were identified in 8 patients. In addition, 2 novel mutations were detected in the GJB1 gene (c.236T>C and c.464T>C). According to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines, both two GJB1 mutations were assigned as 'likely pathogenic'. PMP22 and GJB1 were the most common causative genes in CMT1 and intermediate CMT, respectively. In addition, the first CMTX6 patient with a p.R158H mutation in the PDK3 gene was confirmed in China. Our study further shows that the p.R158H of PDK3 is likely to be a recurrent mutation. Conclusions: The results have broadened the genetic and clinical spectrums of CMT patients, which can help facilitate the diagnosis of CMT. Despite the increasing popularity of NGS, genetic screening of large cohorts of CMT patients using NGS is still rarely performed in the Chinese population. In CMT we suggest having MLPA for PMP22 as the first tier of study followed by target NGS for those with negative MLPA findings. The deciphering of the target gene candidates can further be guided by electromyographic data. [ABSTRACT FROM AUTHOR]

Background: Newborn screening (NBS) aims to detect congenital anomalies, and next‐generation sequencing (NGS) has shown promise in this aspect. However, the NBS strategy for monogenic inherited diseases in China remains insufficient. Methods: We developed a NeoEXOME panel comprising 601 genes that are relevant to the Chinese population found through extensive research on available databases. An interpretation system to grade the results into positive (high‐risk, moderate‐risk, and low‐risk genotypes), negative, and carrier according to the American College of Medical Genetics (ACMG) guidelines was also developed. We validated the panel to evaluate its efficacy by using data from the "1000 Genomes Project" and conducted a pilot multicenter study involving 3423 neonates. Results: The NGS positive rate in the 1000 Genomes Project was 7.6% (23/301), whereas the rate was 12.0% in the multicenter study, including 3249 recruited neonates. Notably, in 200 neonates, positive per conventional NBS, 58.5% (69/118) showed results consistent with NGS. In the remaining 3049 neonates showing negative results in conventional NBS, 271 (8.9%) were positive per NGS, and nine of them were clinically diagnosed with diseases in the follow‐up. Conclusion: We successfully designed a NeoEXOME panel for targeted sequencing of monogenic inherited diseases in NBS. The panel demonstrated high performance in the Chinese population, particularly for the early detection of diseases with no biochemical markers. [ABSTRACT FROM AUTHOR]

Background: Breast cancer, the most prevalent malignancy in women worldwide, presents diverse onset patterns and genetic backgrounds. This study aims to examine the genetic landscape and clinical implications of rare mutations in Chinese breast cancer patients. Methods: Clinical data from 253 patients, including sporadic and familial cases, were analyzed. Comprehensive genomic profiling was performed, categorizing identified rare variants according to the American College of Medical Genetics (ACMG) guidelines. In silico protein modeling was used to analyze potentially pathogenic variants' impact on protein structure and function. Results: We detected 421 rare variants across patients. The most frequently mutated genes were ALK (22.2%), BARD1 (15.6%), and BRCA2 (15.0%). ACMG classification identified 7% of patients harboring Pathogenic/Likely Pathogenic (P/LP) variants, with one case displaying a pathogenic BRCA1 mutation linked to triple-negative breast cancer (TNBC). Also identified were two pathogenic MUTYH variants, previously associated with colon cancer but increasingly implicated in breast cancer. Variants of uncertain significance (VUS) were identified in 112 patients, with PTEN c.C804A showing the highest frequency. The role of these variants in sporadic breast cancer oncogenesis was suggested. In-depth exploration of previously unreported variants led to the identification of three potential pathogenic variants: ATM c.C8573T, MSH3 c.A2723T, and CDKN1C c.C221T. Their predicted impact on protein structure and stability suggests a functional role in cancer development. Conclusion: This study reveals a comprehensive overview of the genetic variants landscape in Chinese breast cancer patients, highlighting the prevalence and potential implications of rare variants. We emphasize the value of comprehensive genomic profiling in breast cancer management and the necessity of continuous research into understanding the functional impacts of these variants. [ABSTRACT FROM AUTHOR]

Background: Expanded carrier screening (ECS) has become a common practice for identifying carriers of monogenic diseases. However, existing large gene panels are not well-tailored to Chinese populations. In this study, ECS testing for pathogenic variants of both single-nucleotide variants (SNVs) and copy number variants (CNVs) in 330 genes implicated in 342 autosomal recessive (AR) or X-linked diseases was carried out. We assessed the differences in allele frequencies specific to the Chinese population who have used assisted reproductive technology (ART) and the important genes to screen for in this population. Methodology: A total of 300 heterosexual couples were screened by our ECS panel using next-generation sequencing. A customed bioinformatic algorithm was used to analyze SNVs and CNVs. Guidelines from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology were adapted for variant interpretation. Pathogenic or likely pathogenic (P/LP) SNVs located in high homology regions/deletions and duplications of one or more exons in length were independently verified with other methods. Results: 64.83% of the patients were identified to be carriers of at least one of 342 hereditary conditions. We identified 622 P/LP variants, 4.18% of which were flagged as CNVs. The rate of at-risk couples was 3%. A total of 149 AR diseases accounted for 64.05% of the cumulative carrier rate, and 48 diseases had a carrier rate above 1/200 in the test. Conclusion: An expanded screening of inherited diseases by incorporating different variant types, especially CNVs, has the potential to reduce the occurrence of severe monogenic diseases in the offspring of patients using ART in China. [ABSTRACT FROM AUTHOR]

Background: Primary ciliary dyskinesia (PCD) is a type of ciliary dyskinesia that is usually caused by autosomal recessive inheritance and can manifest as recurrent respiratory infections, bronchiectasis, infertility, laterality defects, and chronic otolaryngological disease. Although ependymal cilia, which affect the flow of cerebrospinal fluid in the central nervous system, have much in common with respiratory cilia in terms of structure and function, hydrocephalus is rarely associated with PCD. Recently, variants of Forkhead box J1 (FOXJ1) have been found to cause PCD combined with hydrocephalus in a de novo, autosomal dominant inheritance pattern. Methods: We performed DNA extraction, whole‐exome sequencing (WES) analysis, and mutation analysis of FOXJ1 and analyzed the patient's clinical and genetic data. Results: The patient was a 4‐year‐old female exhibiting normal growth and development. At 3 years and 2 months of age, the patient experienced hand shaking and weakness in the lower limbs. Cardiac ultrasonography showed a right‐sided heart, and cranial magnetic resonance imaging showed obstructive hydrocephalus. The nasal nitric oxide level was 54 nL/min. WES indicated a de novo, heterozygous variant of FOXJ1, c.734–735 ins20. This variant was novel, not included in the Human Gene Mutation and Genome Aggregation Database, and likely pathogenic according to the American College of Medical Genetics and Genomics, causing earlier termination of amino acid translation. The patient underwent a neuroendoscopic third ventriculostomy after the diagnosis of obstructive hydrocephalus. Six months after the operation, the patient's motor deficits had improved. Conclusion: This is the first report of a de novo, autosomal dominant pattern of FOXJ1 causing PCD combined with hydrocephalus in China. The patient's clinical symptoms were similar to those previously reported. WES confirmed that a novel variant of FOXJ1 was the cause of the PCD combined with hydrocephalus, expanding the spectrum of the genotypes associated with this condition. Physicians should be aware of the correlation of hydrocephalus and PCD and test for FOXJ1 variants. [ABSTRACT FROM AUTHOR]

Background: Rhizomelic limb shortening with dysmorphic features (RLSDF) has already been a disorder of the rare autosomal recessive skeletal dysplasia, just having a few reported cases. RLSDF is caused by protein kinase domain containing, cytoplasmic(PKDCC)gene variants. In this study, we describe the clinical features and potential RLSDF molecular etiology in a fetus from China. Methods: Genomic DNA (gDNA) extracted from the fetal muscle tissue and parents' peripheral blood was subjected to chromosomal microarray analysis (CMA) and trio-based whole exome sequencing (Trio-WES). The candidate pathogenic variants were verified by using Sanger sequencing. Results: Trio-WES identified two compound heterozygous variants in PKDCC, c.346delC (p.Pro117Argfs*113) and c.994G > T (p.Glu332Ter), inherited from the father and mother, respectively. Both variants are classified as pathogenic according to American College of Medical Genetics and Genomics guidelines. Conclusions: We reported the first prenatal case of RLSDF caused by PKDCC in the Chinese population. Our findings extended the variation spectrum of PKDCC and emphasized the necessity of WES for the early diagnosis of skeletal dysplasia and other ultrasound structural abnormalities in fetuses. [ABSTRACT FROM AUTHOR]

X-linked juvenile retinoschisis (XLRS) is the most common congenital retinoschisis in rare vitreoretinopathy and causes visual disturbances. The study aimed to explore possible genetic mutations associated with XLRS and assess the clinical characteristics in Chinese families. Seventeen cases and thirty-four eyes of probands and thirty-nine cases and seventy-eight eyes of their guardians were recruited. Peripheral blood DNA was extracted and PCR-amplified for retinal disease second-generation panel sequencing to screen for mutated genes. Pathogenicity was referred to the guidelines of the American College of Medical Genetics and Genomics (ACMG). A total of 17 male patients were included, with an average age of 9.73 years (range, 5 ~ 27 years). Clinical data indicate typical macular retinoschisis (97.06%), peripheral retinoschisis (46.67%), retinal holes (32.35%). Fifteen mutations (10 missense mutations, 4 shift mutations, and 3 nonsense mutations) of RS1 gene were identified, including 5 novel mutations. In novel mutations, amino acid conservation analysis shows W33, W50, E62, and G70 were highly conserved, and software predicts mutations to be pathogenic. SWISS-MODEL protein prediction software showed protein structural changes in proband 13. We have identified and described five novel mutations in the RS1 gene and their corresponding clinical manifestations. These findings not only expand the range of known RS1 mutations and associated clinical phenotypes but also provide a basis for mechanistic studies and diagnosis of XLRS. [ABSTRACT FROM AUTHOR]

Introduction: Genetic epilepsy is a large group of clinically and genetically heterogeneous neurological disorders characterized by recurrent seizures, which have a clear association with genetic defects. In this study, we have recruited seven families from China with neurodevelopmental abnormalities in which epilepsy was a predominant manifestation, aiming to elucidate the underlying causes and make a precise diagnosis for the cases. Methods: Whole-exome sequencing (WES) combined with Sanger sequencing was used to identify the causative variants associated with the diseases in addition to essential imaging and biomedical examination. Results: A gross intragenic deletion detected in MFSD8 was investigated via gap-polymerase chain reaction (PCR), real-time quantitative PCR (qPCR), and mRNA sequence analysis. We identified 11 variants in seven genes (ALDH7A1, CDKL5, PCDH19, QARS1, POLG, GRIN2A, and MFSD8) responsible for genetic epilepsy in the seven families, respectively. A total of six variants (c.1408T>G in ALDH7A1, c.1994_1997del in CDKL5, c.794G>A in QARS1, c.2453C>T in GRIN2A, and c.217dup and c.863+995_998+1480del in MFSD8) have not yet been reported to be associated with diseases and were all evaluated to be pathogenic or likely pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Methods: Based on the molecular findings, we have associated the intragenic deletion in MFSD8 with the mutagenesis mechanism of Alu-mediated genomic rearrangements for the first time and provided genetic counseling, medical suggestions, and prenatal diagnosis for the families. In conclusion, molecular diagnosis is crucial to obtain improved medical outcomes and recurrence risk evaluation for genetic epilepsy. [ABSTRACT FROM AUTHOR]

High temperature requirement serine peptidase A1 (HTRA1) related cerebral small vessel disease (CSVD) includes both symptomatic heterozygous HTRA1 variant carrier and cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) patients. Presently, most reported symptomatic heterozygous HTRA1 variant carrier cases are sporadic family reports with a lack of specific characteristics. Additionally, the molecular mechanism of heterozygous HTRA1 gene variants is unclear. We conducted this review to collect symptomatic carriers of heterozygous HTRA1 gene variants reported as of 2022, analyzed all pathogenicity according to American College of Medical Genetics and Genomics (ACMG) variant classification, and summarized the cases with pathogenic and likely pathogenic HTRA1 variants gender characteristics, age of onset, geographical distribution, initial symptoms, clinical manifestations, imaging signs, HTRA1 gene variant information and to speculate its underlying pathogenic mechanisms. In this review, we summarized the following characteristics of pathogenic and likely pathogenic symptomatic HTRA1 variant carriers: to date, the majority of reported symptomatic HTRA1 carriers are in European and Asian countries, particularly in China which was found to have the highest number of reported cases. The age of first onset is mostly concentrated in the fourth and fifth decades. The heterozygous HTRA1 gene variants were mostly missense variants. The two variant sites, 166– 182 aa and 274– 302 aa, were the most concentrated. Clinicians need to pay attention to de novo data and functional data, which may affect the pathogenicity analysis. The decrease in HtrA1 protease activity is currently the most important explanation for the genetic pathogenesis. [ABSTRACT FROM AUTHOR]

Introduction: Luscan-Lumish syndrome (LLS) is currently recognized as a rarelyobserved condition featured with overgrowth, macrocephaly, obesity, type I Chiari malformation, and linguistic retardation. So far, there have been only a few LLS cases registered worldwide, but with none of them reported from China. To acquire a deeper understanding on the clinical and genetic features of this disease, a Chinese boy with LLS caused by a heterozygous variant in SETD2 gene was investigated in the present study. Methods: The patient was clinically examined and the medical history of his family was collected. Genetic testing was performed to determine the genetic etiology. Results: The proband was a boy aged 5-year-7-month-old, who was referred to our hospital due to "being a slow learner in kindergarten". The child had a history of delayed motor and language development in comparison to his peers. After admission, physical examination revealed tall stature and macrocephaly as the major manifestation, in addition to a relatively lower rating in intelligence assessment as well as abnormal MRI images showing a slightly shorter corpus callosum accompanied by a mildly thinner corpus callosum body. Whole exome sequencing (WES) revealed a heterozygous c.2514_2516delTAG (p.Ser838del) variant in SETD2 gene, which was subsequently identified as a novel de novo variant. According to the standardized genetic variant classification published by the American College of Medical Genetics and Genomics (ACMG), the variant, with a pathogenicity analysis result indicating PS2 + PM2_Supporting + PM4, was determined to be likely pathogenic. Through literature review, the clinical phenotypes of the 15 LLS cases were summarized, including 8 cases of overgrowth (53%), 13 cases of macrocephaly (87%), 11 cases of developmental delay (73%), 8 cases of autism (53%), and 7 cases of special facial features (47%). Besides, abnormal craniocerebral MRI findings were noticed in 7 cases. Despite that the mutation sites of the 15 patients varied from case to case, they showed a uniformly distributed pattern throughout the whole SETD2 gene, including 5 missense mutations, 5 frameshift mutations and 5 non-sense mutations. Conclusion: LLS, not having been recognized till recent years, is identified as an autosomal dominant syndrome triggered by SETD2 gene mutation. As the first report of LLS in China, the case in our study was proved to be associated with a unique type of SETD2 gene mutation that has never been reported previously, which is believed to enrich the mutation spectrum of SETD2 gene and also, deepening the clinicians' understanding on the disease. [ABSTRACT FROM AUTHOR]

Background: Neonatal diabetes mellitus (NDM) is a rare form of diabetes. We analyzed a novel insulin gene (INS) mutation of a Chinese permanent neonatal diabetes mellitus (PNDM) patient to explore the clinical and genetic characteristics and put forward some opinions on treatment and its longterm management. Case description: A proband was recruited who was diagnosed with permanent neonatal diabetes on his first day after birth. His clinical and follow-up data were collected for 10 years. All of the family members were given an oral glucose tolerance test. Whole exome sequencing was performed on the proband, and the genomic DNA of family members was used for verification by first-generation Sanger sequencing technology. The pathogenic variant was screened according to the American College of Medical Genetics and Genomics classification guidelines and the clinical phenotype of the patient. Diagnostic assessment: The proband was diagnosed on the first day after birth, presenting with low birth weight, progressive hyperglycemia, and insulin deficiency. His parents and grandfathers were confirmed to have normal blood sugar levels. A novel homozygous mutation of c.1T>C in the INS gene was detected in the proband, located in the initiation codon. The heterozygous mutations were found in four family members, including his mother, father, and grandfathers. With regular insulin injections, long-term regular follow-up, close monitoring of blood glucose, balanced exercise and diet, and psychological and mutual family support, the blood glucose level was well controlled; there were no acute or chronic complications during this decade. The patient's growth and nervous system development are now no different to those of the same age. Conclusion: A favorable prognosis is presented for a permanent neonatal diabetes mellitus (PNDM) patient with a novel mutation in the INS gene in China. The present findings indicate that the genetic diagnosis, early use of insulin, close monitoring of blood glucose, and psychological and mutual family support for patients with INS mutation are necessary for their favorable long-term prognosis. [ABSTRACT FROM AUTHOR]

Background: This study was to reveal the prevalence of definite familial hypercholesterolemia (FH) in the hospital‐visiting population, determine the pathogenic mutation detection rate in clinically diagnosed definite FH patients, and expand the FH mutation spectrum in China. Methods: Blood lipid profiles of 41,803 patients visiting the hospital were investigated and 4967 patients with clinical diagnoses of other metabolic diseases were excluded. One hundred and seventy‐three (0.41%) received a definite diagnosis of FH according to the Dutch Lipid Clinical Network Criteria‐Chinese Revised Version (DLCN‐CRV), and 18 patients subsequently agreed to undergo genetic testing. A next‐generation sequencing (NGS)‐based laboratory‐developed test covering the exonic regions of 24 lipid metabolism‐related genes was conducted alongside in silico analyses to identify possible FH mutations in 16 definite FH patients, according to the American College of Medical Genetics and Genomics (ACMG) criteria. Sanger sequencing was used to confirm mutations, and SWISS‐MODEL was used to simulate the molecular structures of the confirmed protein‐carrying mutations. Results: The FH prevalence was 0.41% for the 41,803 individuals (DLCN‐CRV grade >8) and 25% of definite FH patients carried six FH pathogenic mutations (≥ACMG Class 4). All genetic variants were confirmed by Sanger sequencing. Five pathogenic variants on the LDLR gene (NM_000527: c.C1783T: p.R595W, c.T493G: p.W165G, c.G1879A: p.A627T, c.G682T: p.E228X, and exon10: c.G1432A: p.G478R) and one pathogenic variant on APOB (NM_000384: c.C10579T: p.R3527W) in 25% of the identified definite FH patients. Two pathogenic mutations, c.T493G (p.W165G) and c.C1783T (p.R595W), were added to the current genetic spectrum of FH in China. Conclusion: This study contributes to improving the current FH detection rate and genetic screening strategies; it provides new directions for treatment, management, and drug development. [ABSTRACT FROM AUTHOR]

From Mendel's discovery of the basic laws of genetics in 1865 to the widespread application of genomics in medicine today, medical genetics has made enormous progress, and the concept of genetic diseases has also been evolved. In 1972, the World Health Organization (WHO) expert group began to use "Genetic Disease" to define hereditary diseases, while early Chinese genetics textbooks used "inferior inheritance", and later introduced terms such as "Genetic Disease" and "Inherited Disease". In the early days, it was generally believed that genetic diseases were inherited from ancestors. However, research in recent years has found that genetic diseases are not necessarily inherited, and some diseases are actually caused by de novo mutations in the offspring. Although the occurrence of this type of genetic disease is related to genetic factors, it is not inherited from ancestors. If we still use "Inherited Disease" or "Hereditary Disease" to describe it, it is not accurate enough. In order to further standardize the translation and use of the concept of "Genetic Disease", this article briefly reviews its development process in both English and Chinese literature, discusses the difference between different Chinese translations, and provides guidance and suggestions for scientifically and accurately describing genetic diseases in Chinese, with a view to promote efficient exchange and cooperation in the field of medical genetics.

Background: CHARGE syndrome (CS) is a single-gene genetic disorder with multiple organ malformations caused by a variant of the chromodomain helicase DNA-binding protein 7 (CHD7) gene on chromosome 8q12.1. In this study, we aimed to investigate new variants that have emerged in these cases compared with typical CS and the relationship between the genes and phenotypes. Methods: Patients with suspected genetic diseases were subjected to Whole Exome Sequencing (WES) at a genetics laboratory in Guangzhou. The average sequencing coverage depth was >200 ×, and 96% was >20 ×. The variant interpretation was manipulated according to the American College of Medical Genetics (ACMG) guidelines. Molecular data on databases for ClinVar and CHD7 were also collected and collated. We reviewed the currently described CHD7 variants and analyzed the genetic variation and phenotypic heterogeneity. Results: Data of 12 patients with CS from four hospitals in China were collected. According to gestational age, most of them (8/12) were near-term babies with a lower birth weight than their peers, averaging 2.62 kg. In this study, the most common phenotypes were respiratory tract malformations (11/12), heart malformations (10/12), and central nervous system malformations (9/12). Two fetuses were confirmed to have brain or heart abnormalities during prenatal testing, while 10/12 were found to have abnormalities during prenatal testing. The maximum Acute Physiology and Chronic Health Evaluation (APACHE II) score at admission was 19, and the average was 11.58. Five variants in the CHD7 gene c.7012C > T (p.Q2338*), c.7868delC (p.P2623Rfs*16), c.5405-3C > G, c.6936 + 2T > C, and c.8077-2A > G) were novel and were located in exons 33, 36, and introns 25, 32, and 37, respectively. There may be a positive correlation between exon location and phenotype. Conclusion: Five novel variants were discovered. These expanded the mutational spectrum of the CHD7 gene and the phenotype of CS. There may be a correlation between the new mutation sites and the phenotype, which has some reference value for the evaluation of mutation sites. [ABSTRACT FROM AUTHOR]

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Background: Oculocutaneous albinism (OCA) is a group of heterogeneous genetic diseases characterized by a reduction or complete lack of pigmentation in the hair, skin, and eyes. It is associated with reduced visual acuity, nystagmus, photophobia, and strabismus. OCA type 1 (OCA1) and type 2 (OCA2) are caused by mutations in the tyrosinase (TYR) and OCA2 genes, which are responsible for most cases of OCA. The present study aimed to identify the mutational spectra of 18 southwest Chinese probands with OCA. Results: We used a skin disease-targeted panel to sequence more than 400 genes, including 23 genes (TYR, OCA2, AP3B1, BLOC1S3, BLOC1S6, C10orf11, DTNBP1, FRMD7, GPR143, HPS1, HPS3, HPS4, HPS5, HPS6, LYST, MC1R, MITF, MLPH, MYO5A, RAB27A, SLC24A5, SLC45A2, TYRP1) associated with syndromic and non-syndromic albinism. The targeted panel was applied to 18 patients from southwest China, nine (50%) patients were diagnosed with OCA1, and nine (50%) were diagnosed with OCA2. Our data indicate that OCA1 and OCA2, the most common subtypes, probably have the same prevalence in southwest China. In total, we identified 26 variants in TYR and OCA2 from 18 OCA cases using the NGS technology, including 24 variants presented in the Human Gene Mutation Database Professional (HGMD) and two novel variants, c.559_560insCATTATTATGTGTCAAATTATCCCC in TYR and c.1514 T > C in OCA2, which have not been previously reported. According to the American College of Medical Genetics and Genomics (ACMG) classification, c.559_560insCATTATTATGTGTCAAATTATCCCC (p.G190Cfs*12) is classified as a pathogenic variant, and c.1514 T > C (p.F505S) is evaluated as a likely pathogenic variant. Conclusions: Two novel variants were identified which will expand the mutational spectra of TYR and OCA2. The results of the present study may have implications for genetic counseling, carrier screening, and clinical management of the disease. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate inter-laboratory classification concordance for copy number variants (CNVs) with a semiquantitative point-based scoring metric recommended by the American College of Medical Genetics and Genomics (ACMG) and Clinical Genome Resources (ClinGen). A total of 234 CNVs distributed by the National Center of Clinical Laboratories (NCCLs), and 72 CNVs submitted by different laboratories, were distributed to nine clinical laboratories performing routine clinical CNV testing in China and independently classified across laboratories. The overall inter-laboratory complete classification concordance rate of the 234 distributed CNVs increased from 18% (41/234) to 76% (177/234) using the scoring metric compared to the laboratory's previous method. The overall inter-laboratory complete classification concordance rate of the 72 submitted CNVs was 65% (47/72) using the scoring metrics. The 82 variants that initially did not reach complete concordance classification and 1 additional CNV deletion were reviewed; 34 reached complete agreement, and the overall post-review complete concordance rate was 85% (260/306). Additionally, the overall percentage of classification discordance possibly impacting medical management [i.e., pathogenic (P) or likely pathogenic (LP) vs. variant of uncertain significance (VUS)] was 11% (35/306). The causes of initial and final discordance in the classification were identified. The ACMG-ClinGen framework has promoted consistency in interpreting the clinical significance of CNVs. Continuous training among laboratories, further criteria and additional clarification of the standards, sharing classifications and supporting evidence through public database, and ongoing work for dosage sensitive genes/regions curation will be beneficial for harmonization of CNVs classification. [ABSTRACT FROM AUTHOR]

Purpose: X-linked juvenile retinoschisis (XLRS), caused by mutations in the RS 1 gene, is an X-linked recessive inherited disease that typically involves both eyes in the first 2 decades of life. Recently, the phenotype heterogeneity of this condition has drawn increasing attention. We reported various phenotypes caused by RS1 gene mutations in eleven patients from ten Chinese families. Methods: Data on the medical history of the patients from ten Han families of central China were collected. Ophthalmic examinations including best-corrected visual acuity (BCVA), fundus photography, ultra-wide-angle sweep source optical coherence tomography (SS-OCT), and electroretinography (ERG) were performed. Adaptive optics (AO) images were acquired to evaluate the cone photoreceptor mosaic when applicable. Venous blood of the probands and their family members was collected, and DNA was subjected to sequencing based on next-generation sequencing with a custom-designed targeted gene panel PS400 for inherited retinal diseases. Validation was performed by Sanger sequencing and cosegregation. Pathogenicity was determined in accordance with the American College of Medical Genetics and Genomics (ACMG) guidelines. Results: Ten RS1 mutations, including eight missense mutations and two terminator mutations, were identified in 10 XLRS families. c.657C > A (p.C219X) was a novel mutation in this cohort. These patients showed a variety of clinical phenotypes, including fovea schisis, bullous retinoschisis, and macular or peripheral atrophy. Fifteen eyes of eight patients exhibited macular retinoschisis, and twelve eyes of seven patients exhibited peripheral retinoschisis. In addition, three patients showed asymmetrical fundus manifestations. Of importance, three patients without macular retinoschisis were misdiagnosed until genetic testing results were obtained. AO showed a decrease in cone density and loss of regularity in the cystic schisis macular of XLRS. Furthermore, the BCVA was associated with the photoreceptor inner segment and outer segment (IS/OS) thickness. Conclusion: With complicated clinical manifestations, a considerable portion of XLRS patients may present various phenotypes. It should be noted that asymmetry in fundus appearance in both eyes could lead to misdiagnosis easily. Thus, genetic testing is crucial for making a final diagnosis in those patients who are suspected of having amblyopia, bilateral or unilateral macular atrophy, or conditions presenting an asymmetric fundus appearance. In addition, the residual cone photoreceptor structure was critical for the maintenance of useful vision. [ABSTRACT FROM AUTHOR]

In clinical genetic testing, checking the concordance between self-reported gender and genotype-inferred gender from genomic data is a significant quality control measure because mismatched gender due to sex chromosomal abnormalities or misregistration of clinical information can significantly affect molecular diagnosis and treatment decisions. Targeted gene sequencing (TGS) is widely recommended as a first-tier diagnostic step in clinical genetic testing. However, the existing gender-inference tools are optimized for whole genome and whole exome data and are not adequate and accurate for analyzing TGS data. In this study, we validated a new gender-inference tool, seGMM, which uses unsupervised clustering (Gaussian mixture model) to determine the gender of a sample. The seGMM tool can also identify sex chromosomal abnormalities in samples by aligning the sequencing reads from the genotype data. The seGMM tool consistently demonstrated >99% gender-inference accuracy in a publicly available 1,000-gene panel dataset from the 1,000 Genomes project, an in-house 785 hearing loss gene panel dataset of 16,387 samples, and a 187 autism risk gene panel dataset from the Autism Clinical and Genetic Resources in China (ACGC) database. The performance and accuracy of seGMM was significantly higher for the targeted gene sequencing (TGS), whole exome sequencing (WES), and whole genome sequencing (WGS) datasets compared to the other existing gender-inference tools such as PLINK, seXY, and XYalign. The results of seGMM were confirmed by the short tandem repeat analysis of the sex chromosome marker gene, amelogenin. Furthermore, our data showed that seGMM accurately identified sex chromosomal abnormalities in the samples. In conclusion, the seGMM tool shows great potential in clinical genetics by determining the sex chromosomal karyotypes of samples from massively parallel sequencing data with high accuracy. [ABSTRACT FROM AUTHOR]

Background: Branchio-oto-renal syndrome (BOR) and branchio-oto syndrome (BOS) are rare autosomal dominant disorders defined by varying combinations of branchial, otic, and renal anomalies. Here, we characterized the clinical features and genetic etiology of BOR/BOS in several Chinese families and then explored the genotypes and phenotypes of BOR/BOS-related genes, as well as the outcomes of auditory rehabilitation in different modalities. Materials and Methods: Probands and all affected family members underwent detailed clinical examinations. Their DNA was subjected to whole-exome sequencing to explore the underlying molecular etiology of BOR/BOS; candidate variants were validated using Sanger sequencing and interpreted in accordance with the American College of Medical Genetics guidelines. In addition, a literature review concerning EYA1 and SIX1 alterations was performed to explore the genotypes and phenotypes of BOR/BOS-related genes. Results: Genetic testing identified the novel deletion (c.1425delC, p(Asp476Thrfs*4); NM_000,503.6), a nonsense variant (c.889C > T, p(Arg297*)), and two splicing variants in the EYA1 gene (c.1050+1G > T and c.1140+1G > A); it also identified one novel missense variant in the SIX1 gene (c.316G > A, p(Val106Met); NM_005,982.4). All cases exhibited a degree of phenotypic variability between or within families. Middle ear surgeries for improving bone-conduction component hearing loss had unsuccessful outcomes; cochlear implantation (CI) contributed to hearing gains. Conclusion: This is the first report of BOR/BOS caused by the SIX1 variant in China. Our findings increase the numbers of known EYA1 and SIX1 variants. They also emphasize the usefulness of genetic testing in the diagnosis and prevention of BOR/BOS while demonstrating that CI for auditory rehabilitation is a feasible option in some BOR/BOS patients. [ABSTRACT FROM AUTHOR]

Backgbround: Frontotemporal dementia (FTD) is the second most common presenile dementia, characterized by prominent behavioral, language, and cognitive impairment, which has a strong genetic component contributing to its pathogenesis. Due to geographical and ethnic variability, the prevalence of the causative genes of FTD may be different. Methods: To explore the genetics of FTD in the Chinese population, we reviewed 97 closely related studies that were searched in PubMed and Web of Science. In this review, we summarized the characteristics of each FTD gene. We also reassessed their pathogenicity and revised some mutations from pathogenic to uncertain significance according to the American College of Medical Genetics and Genomics (ACMG). Results: Thirty-two rare variants in genes of MAPT, GRN, C9orf72, CHCHD10, VCP, and TBK1 were identified in Chinese FTD populations, including 25 pathogenic mutations and seven variants of uncertain significance (VUS). Among them, the frequency of rare variants in the CHCHD10 gene was the highest. Surprisingly, twelve variants reported as pathogenic mutations were revised as VUS by ACMG. The correlations between genes and clinical manifestations were MAPT and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), GRN and frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP), C9orf72/CHCHD10/TBK1 and amyotrophic lateral sclerosis (ALS)-FTD spectrum, and VCP corresponds inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD). Conclusions: It is necessary to strictly interpret the contributions of genes to diseases by ACMG. MAPT is the most common pathogenic gene for FTD in China. [ABSTRACT FROM AUTHOR]

Purpose: Leber congenital amaurosis (LCA) is one of the earliest inherited retinal dystrophies (IRD) that leads to blindness. To date, there have been 25 LCA-associated genes reported in China as well as other countries. The current study aimed to present the dominant molecular genetics and clinical features of LCA in the Han population of western China. Methods: Our study comprised 37 patients with strictly defined Leber congenital amaurosis in a cohort of IRD (2009–2019). The mutations were detected by targeted next-generation sequencing (NGS), Sanger sequencing, and segregation analysis. The patients underwent comprehensive clinical examinations, analysis of phenotypes and genotypes. Results: Out of the 37 patients, 34 harbored known LCA genes; the detection rate of mutations was 91.9%. Forty-seven different alleles incorporated 21 novel mutations; 8 were known LCA-associated genes. The three most frequently mutated genes included CRB1 (27.0%), RDH12 (24.3%), and RPGRIP1 (18.9%). The CRB1-associated LCA showed a pigmented fundus; the RDH12-associated LCA featured macular atrophy. Our results revealed that CRB1 and RPGRIP1 genes occupied a greater proportion in the western Chinese population. The proportion of these two genes was similar in other regions of China as well. The difference existed in a larger proportion of RDH12-associated LCA in the western Chinese population. Conclusions: The new findings in our study group polished the spectrum of the novel mutations and phenotypes of LCA with regional and ethnic variations. This comprehensive database can provide essential information for gene therapies. [ABSTRACT FROM AUTHOR]

Keywords: Asians; cardiomyopathy, hypertrophic; genetic testing; hypertrophy EN Asians cardiomyopathy, hypertrophic genetic testing hypertrophy 2086 2089 4 11/25/20 20201124 NES 201124 Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disorder characterized by unexplained left ventricular hypertrophy.[1] Although considered as a dominant Mendelian disease mainly caused by rare pathogenic variants in sarcomere genes, the genetic underpinnings of nearly half of patients remain unsolved.[2] Increasing evidence implies that HCM has a more complex genetic architecture.[3] We identified an East Asian-specific common missense variant in I TNNI3 i (rs3729712) associated with HCM in an exome-wide case-control association study of Chinese origin and replicated the finding in 3 independent studies ( I P i =5.80×10 SP -22 sp ). The association was confirmed in each of the 3 replication studies, among which the Beijing replication samples and Xi'an-1 cases were genotyped by a panel sequencing of cardiomyopathy candidate genes, and the Xi'an-1 controls and Xi'an-2 samples by Sanger sequencing. Patients with HCM were classified into SARC+ (pathogenic or likely pathogenic variant identified in a sarcomere gene) and SARC- (no potentially pathogenic variant identified in a sarcomere gene) groups by the presence of any variant of pathogenic, likely pathogenic, or unknown significance in the 8 sarcomere genes (MYH7, MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, and ACTC1) in the discovery study (495 vs 491), Beijing replication study (226 vs 303), and Xi'an-1 study (342 vs 304). [Extracted from the article]

Background: Hemophilia B (HB) is an X‐linked recessive inherited bleeding disorder caused by mutations in the F9 gene that lead to plasma factor IX deficiency. To identify the causative mutations in HB, a molecular analysis of HB pedigrees in China was performed. Methods: Using next‐generation sequencing (NGS) and an in‐house bioinformatics pipeline, 76 unrelated HB pedigrees were analyzed. The mutations identified were validated by comparison with the results of Sanger sequencing or Multiplex Ligation‐dependent Probe Amplification assays. The pathogenicity of the causative mutations was classified following the American College of Medical Genetics and Genomics guidelines. Results: The mutation detection rate was 94.74% (72/76) using NGS. Of the 76 HB pedigrees analyzed, 59 causative variants were found in 72 pedigrees, with 38 (64.41%) missense mutations, 9 (15.25%) nonsense mutations, 2 (3.39%) splicing mutations, 5 (8.47%) small deletions, 4 (6.78%) large deletions, and 1 intronic mutation (1.69%). Of the 59 different F9 mutations, 10 were novel: c.190T>G, c.199G>T, c.290G>C, c.322T>A, c.350_351insACAATAATTCCTA, c.391+5delG, c.416G>T, c.618_627delAGCTGAAACC, c.863delA, and c.1024_1027delACGA. Of these 10 novel mutations, a mosaic mutation, c.199G>T(p.Glu67Ter), was identified in a sporadic HB pedigree. Using in‐silico analysis, these novel variants were predicted to be disease‐causing. However, no potentially causative mutations were found in the F9 coding sequences of the four remaining HB pedigrees. In addition, two HB pedigrees carrying additional F8/F9 mutations were discovered. Conclusion: The identification of these mutations enriches the spectrum of F9 mutations and provides further insights into the pathogenesis of HB in the Chinese population. [ABSTRACT FROM AUTHOR]

Amyloid protein deposition is a common mechanism of hereditary amyloidosis (HA) and Alzheimer's disease (AD). Mutations of g elsolin (GSN), cystatin C (CST3), transthyretin (TTR), and integral membrane protein 2B (ITM2B) genes can lead to HA. But the relationship is unclear between these genes and AD. Genes targeted sequencing (GTS), including GSN, CST3, TTR , and ITM2B , was performed in a total of 636 patients with clinical AD and 365 normal controls from China. As a result, according to American College of Medical Genetics and Genomics (ACMG) guidelines, two novel likely pathogenic frame-shift mutations (GSN:c.1036delA:p.K346fs and GSN:c.8_35del:p.P3fs) were detected in five patients with AD, whose initial symptom was memory decline, accompanied with psychological and behavioral abnormalities later. Interestingly, the patient with K346fs mutation, presented cerebral β-amyloid protein deposition, had an early onset (48 years) and experienced rapid progression, while the other four patients with P3fs mutation had a late onset [(Mean ± SD): 69.50 ± 5.20 years] and a long course of illness [(Mean ± SD): 9.24 ± 4.86 years]. Besides, we also discovered 17 variants of uncertain significance (VUS) in these four genes. To our knowledge, we are the first to report AD phenotype with GSN mutations in patients with AD in the Chinese cohort. Although mutations in the GSN gene are rare, it may explain a small portion of clinically diagnosed AD. [ABSTRACT FROM AUTHOR]

This study aimed to determine the mutational spectrum of familial Parkinson's disease and sporadic early-onset Parkinson's disease (sEOPD) in a mainland Chinese population and the clinical features of mutation carriers. We performed multiplex ligation-dependent probe amplification assays and whole-exome sequencing for 1676 unrelated patients with Parkinson's disease in a mainland Chinese population, including 192 probands from families with autosomal-recessive Parkinson's disease, 242 probands from families with autosomal-dominant Parkinson's disease, and 1242 sEOPD patients (age at onset ≤ 50). According to standards and guidelines from the American College of Medical Genetics and Genomics, pathogenic/likely pathogenic variants in 23 known Parkinson's disease-associated genes occurred more frequently in the autosomal-recessive Parkinson's disease cohort (65 of 192, 33.85%) than in the autosomal-dominant Parkinson's disease cohort (10 of 242, 4.13%) and the sEOPD cohort (57 of 1242, 4.59%), which leads to an overall molecular diagnostic yield of 7.88% (132 of 1676). We found that PRKN was the most frequently mutated gene (n = 83, 4.95%) and present the first evidence of an SNCA duplication and LRRK2 p.N1437D variant in mainland China. In addition, several novel pathogenic/likely pathogenic variants including LRRK2 (p.V1447M and p.Y1645S), ATP13A2 (p.R735X and p.A819D), FBXO7 (p.G67E), LRP10 (c.322dupC/p.G109Rfs*51) and TMEM230 (c.429delT/p.P144Qfs*2) were identified in our cohort. Furthermore, the age at onset of the 132 probands with genetic diagnoses (median, 31.5 years) was about 14.5 years earlier than that of patients without molecular diagnoses (i.e. non-carriers, median 46.0 years). Specifically, the age at onset of Parkinson's disease patients with pathogenic/likely pathogenic variants in ATP13A2, PLA2G6, PRKN, or PINK1 was significantly lower than that of non-carriers, while the age at onset of carriers with other gene pathogenic/likely pathogenic variants was similar to that of non-carriers. The clinical spectrum of Parkinson's disease-associated gene carriers in this mainland Chinese population was similar to that of other populations. We also detected 61 probands with GBA possibly pathogenic variants (3.64%) and 59 probands with GBA p.L444P (3.52%). These results shed insight into the genetic spectrum and clinical manifestations of Parkinson's disease in mainland China and expand the existing repertoire of pathogenic or likely pathogenic variants involved in known Parkinson's disease-associated genes. Our data highlight the importance of genetic testing in Parkinson's disease patients with age at onset < 40 years, especially in those from families with a recessive inheritance pattern, who may benefit from early diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Background: Phenomics provides new technologies and platforms as a systematic phenome-genome approach. However, few studies have reported on the systematic mining of shared genetics among clinical biochemical indices based on phenomics methods, especially in China. This study aimed to apply phenomics to systematically explore shared genetics among 29 biochemical indices based on the Fangchenggang Area Male Health and Examination Survey cohort. Result: A total of 1999 subjects with 29 biochemical indices and 709,211 single nucleotide polymorphisms (SNPs) were subjected to phenomics analysis. Three bioinformatics methods, namely, Pearson's test, Jaccard's index, and linkage disequilibrium score regression, were used. The results showed that 29 biochemical indices were from a network. IgA, IgG, IgE, IgM, HCY, AFP and B12 were in the central community of 29 biochemical indices. Key genes and loci associated with metabolism traits were further identified, and shared genetics analysis showed that 29 SNPs (P < 10− 4) were associated with three or more traits. After integrating the SNPs related to two or more traits with the GWAS catalogue, 31 SNPs were found to be associated with several diseases (P < 10− 8). Using ALDH2 as an example to preliminarily explore its biological function, we also confirmed that the rs671 (ALDH2) polymorphism affected multiple traits of osteogenesis and adipogenesis differentiation in 3 T3-L1 preadipocytes. Conclusion: All these findings indicated a network of shared genetics and 29 biochemical indices, which will help fully understand the genetics participating in biochemical metabolism. [ABSTRACT FROM AUTHOR]

Non‐syndromic oculocutaneous albinism (nsOCA) is a group of genetically heterogeneous autosomal recessive disorders with complete lack or decrease pigmentation in skin, hair, and eyes. TYR, OCA2, TYRP1, SLC45A2, SLC24A5, and LRMDA were reported to cause OCA1‐4 and OCA6‐7, respectively. By sequencing all the known nsOCA genes in 114 unrelated Chinese nsOCA patients combined with In silico analyses, splicing assay, and classification of variants according to the standards and guidelines of American College of Medical Genetics and Genomics, we detected seventy‐one different OCA‐causing variants separately in TYR, OCA2, SLC45A2, and SLC24A5, including thirty‐one novel variants (13 in TYR, 11 in OCA2, and 7 in SLC45A2). This study shows that OCA1 is the most common (75/114) and OCA2 ranks the second most common (16/114) in Chinese. 99 patients of our cohort were caused by variants of all the known nsOCA genes. Cutaneous phenotypes of OCA1, OCA2, and OCA4 patients were shown in this study. The second OCA6 case in China was identified here. These data expand the spectrum of OCA variants as well phenotype and facilitate clinical implement of Chinese OCA patients. [ABSTRACT FROM AUTHOR]

Distal hereditary motor neuropathy (dHMN) is a clinically and genetically heterogeneous group of inherited neuropathies characterized by distal limb muscle wasting and weakness with no or minimal sensory abnormalities. To investigate the clinical and genetic features of dHMN caused by WARS mutations in mainland China, we performed Sanger sequencing of the coding and untranslated region (UTR) regions of WARS in 160 unresolved dHMN and Charcot‐Marie‐Tooth (CMT) index patients. We detected a novel heterozygous variant c.941A>G (p.Asp314Gly) of WARS in an index patient from an autosomal dominant dHMN family including five affected members over three generations. The variant completely co‐segregates with the dHMN phenotype in the family, and it was classified as likely pathogenic according to the American College of Medical Genetics and Genomics standards and guidelines. The clinical features included juvenile to adult onset (15‐23 years), distal wasting and weakness, minimal sensory disturbance and length‐dependent motor axonal degeneration with CMT examination score ranging from 6 to 10. Our report further confirms the role of WARS in dHMN and indicates that the variant c.941A>G (p.Asp314Gly) of WARS is related to a mild to moderate affected and later onset phenotype of dHMN. [ABSTRACT FROM AUTHOR]

Background: Dystonia is a movement disorder with high clinical and genetic heterogeneity. Recently mutations in lysine-specific histone methyltransferase 2B (KMT2B) gene have been reported to be associated with early-onset progressive dystonia. Methods: We performed whole-exome sequencings (WES) in a cohort of early-onset dystonia patients from China. Bioinformatics analysis and cosegregation testings were conducted to select candidate causal variants. The effects of identified variants were classified according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines. Results: Three novel KMT2B variants were identified, including p.Q1359* in patient 1, p.R1487AfsTer7 in patient 2, and p.R152W in patient 3. Among these variants, the nonsense variant p.Q1359* and the frameshift variant p.R1487AfsTer7 showed high pathogenicity and were rated as pathogenic according to the ACMG guideline. Regarding the phenotypes of these two patients with pathogenic variants, patient 2 showed the similar presentation as reported whereas patient 1 seemly harbored the atypical presentations, including later onset age, atypical sites of onset and milder degree of dystonia. Conclusions: We further report three dystonia patients with novel variants in KMT2B and expand the spectrums of genotype and phenotype of KMT2B. [ABSTRACT FROM AUTHOR]

Introduction: Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism due to ATP7B pathogenic mutations. Disease manifestations can be prevented if early diagnosis and effective treatment are given. Direct sequencing is routinely used to confirm WD diagnosis, but cannot identify gross rearrangements.Methods: Sanger sequencing of ATP7B was performed in 142 newly recruited WD index patients. The clinical effects of identified variants were classified according to American College of Medical Genetics and Genomics (ACMG) standards and guidelines. Multiplex ligation-dependent probe amplification (MLPA) was performed in 168 WD cases with clinical WD unexplained by Sanger sequencing, selected from our total case series of 774 WD patients. After identifying gross rearrangements within ATP7B, the breakpoints were determined by long-range PCR and direct sequencing.Results: In the 142 WD patients, we identified 71 sequence alterations in ATP7B, of which 15 were novel; 14 of these were classified as 'pathogenic' or 'likely pathogenic', including 2 intronic variants affecting splice sites. In 6 of 168 WD patients, MLPA identified four heterozygous gross ATP7B deletions. One was a whole gene deletion, and three were intragenic deletions which were mapped to breakpoint locations, revealing non-homologous end joining.Conclusion: Intragenic deletions are responsible for WD and non-homologous end joining could be the pathogenesis, therefore the detection of intragenic deletions should be included in comprehensive genetic testing for WD. [ABSTRACT FROM AUTHOR]

Objectives To look at the possible effect of IGF2R rs9456497 on cardiovascular risks in a long-lived population. Methods IGF-2R rs9456497 was genotyped by iMLDR for 496 long-lived Zhuang Chinese (90–107 y/o) and their offspring (n = 723, 60–75 y/o) and healthy controls (n = 611, 60–75 y/o). Association analyses were then conducted among genotypes and cardiovascular risks. Results The G genotype (GA/GG) was found to represent more frequently in males of general population. No significantly difference was detected among genotypes in each group except that G genotype tended to reduce the systolic blood pressure (SBP) and diastolic blood pressure (DBP) levels in longevity group. However, after sex stratification, total cholesterol (TC) of each genotype in offspring males was elevated versus relevant genotype in longevity and control group; the triglyceride (TG), fasting plasma glucose (FPG) and BMI of each genotype in longevity group were lower while SBP and DBP were higher than that of the relevant genotype in offspring and controls. After stratified by lipid status, the frequency of G allele was markedly increased in the dyslipidemic subgroup in the combined population and controls. Linear regressive analyses showed that HDL was positively correlated to rs9456497 GA genotype while BMI was negatively correlated to AA genotype in offspring group, whereas TC and TG were reversely while BMI was positively associated with AA genotype in CG. Conclusions IGF-2R rs9456497 G genotype correlates to detrimental cardiovascular risks in ordinary population which might partially interpret their less preservation of health as compared to long-lived cohort. [ABSTRACT FROM AUTHOR]

Backgrund/aim: There is a very high prevalence of gout in the Minnan population in China. We aimed to explore the genetic characteristics and genetic mechanisms of gout in the Minnan population by studying the association of 5 single nucleotide polymorphisms (SNPs) with gout. Materials and methods: A total of 163 gout patients and 187 normal controls from Minnan were enrolled in this case-control study. SNPs (rs1165205, rs3733591, rs6855911, rs2231142, rs333049) were genotyped by allele-specific polymerase chain reaction (PCR) and analyzed with SPSS 16.0. Results: Significant association with gout was found for rs2231142 (P < 0.001), consistent with our prior studies. An association between rs1333049 and gout was also found (P = 0.03) in the Minnan population. No association of SNPs rs6855911, rs3733591, and rs1165205 was found with gout in the Minnan population. Conclusions: Rs1333049 is associated with gout in the Minnan population, although rs2231142 shows an even stronger association with gout. The C allele of rs1333049 and the A allele of rs2231142 might be crucial risk factors for gout. [ABSTRACT FROM AUTHOR]

Background: Dyschromatosis symmetrica hereditaria (DSH) is a rare autosomal dominant cutaneous disorder caused by the mutations of adenosine deaminase acting on RNA1 (ADAR1) gene. We present a clinical and genetic study of seven unrelated families and two sporadic cases with DSH for mutations in the full coding sequence of ADAR1 gene. Methods: ADAR1 gene was sequenced in seven unrelated families and two sporadic cases with DSH and 120 controls. Functional significance of the observed ADAR1 mutations was analyzed using PolyPhen 2, SIFT and DDIG-in. Results: We describe six novel mutations of the ADAR1 gene in Chinese patients with DSH including a nonstop mutation p.Stop1227R, which was firstly reported in ADAR1 gene. In silico analysis proves that all the mutations reported here are pathogenic. Conclusion: This study is useful for functional studies of the protein and to define a diagnostic strategy for mutation screening of the ADAR1 gene. A three-generation family exhibiting phenotypic variability with a single germline ADAR1 mutation suggests that chilblain might aggravate the clinical phenotypes of DSH. [ABSTRACT FROM AUTHOR]

Western observational studies show that moderate alcohol use is associated with lower cardiovascular disease (CVD) risk, but these associations may be confounded by the healthier attributes of moderate users in these settings. Mendelian randomization analysis may help to ascertain the causal effect of moderate alcohol use on specific factors related to CVD and thereby clarify the role of alcohol. We used Mendelian randomization analysis with the aldehyde dehydrogenase 2 gene (ALDH2) as an instrumental variable to examine the association of alcohol units (10 g of ethanol) per day with heart rate-corrected QT interval and heart rate assessed from electrocardiogram among 4,588 older southern Chinese men in the Guangzhou Biobank Cohort Study (2003-2008). The Fstatistic was 77 for ALDH2 on alcohol use, suggesting little weak-instrument bias. Instrumental variable analysis showed that alcohol units were not associated with the corrected QT interval, with β = 1.04 (95% confidence interval: -0.61, 2.70) milliseconds, but they were associated with increased heart rate, with β = 0.98 (95% confidence interval: 0.04, 1.92) beat per minute. This study suggests that moderate alcohol use in men is not beneficial for heart function via QT interval or heart rate but could be detrimental. Future studies using specific cardiovascular outcomes may elucidate how alcohol affects different aspects of the cardiovascular system and, hence, the overall effects of alcohol on CVD can be estimated. [ABSTRACT FROM AUTHOR]

Abstract: Toxoplasma gondii can infect a wide variety of warm-blooded animals, including bats. Limited information on T. gondii infection in bats is available in China. The objective of the present study was to determine prevalence and genetic diversity of T. gondii infection in bats in southern China. A total of 608 bats representing 12 species, including 120 Aselliscus stoliczkanus, 59 Myotis chinensis, 11 Miniopterus schreibersii, 53 Rhinolophus affinis, 32 Rhinolophus pusillus, 81 Hipposideros armiger, 28 Hipposideros fulvus, 32 Cynopterus brachyotis, 14 Cynopterus sphinx, 45 Eonycteris spelaea, 109 Hipposideros larvatus, and 24 Taphozous melanopogon, were collected from Yunnan and Guangxi provinces, southern China. They were examined for the presence of T. gondii DNA by amplification of the B1 gene using a nested PCR, and the positive samples were genotyped at 11 genetic loci (SAG1, 5′- and 3′-SAG2, alternative SAG2, SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1 and Apico) using multilocus polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technology. Fifty-nine (9.7%) of these bats were detected positive by PCR but only five of these positive DNA samples were completely typed at all loci; of which 4 samples, 2 from A. stoliczkanus, and 2 from H. larvatus, belonged to ToxoDB Genotype #10, and the other one from H. larvatus was identified as ToxoDB Genotype #9 (http://toxodb.org/toxo/). To our knowledge, this is the first report of molecular detection and genetic characterization of T. gondii infection in bats in China. The results show that these bats are potential reservoirs for T. gondii transmission, which may pose a threat to human health. [Copyright &y& Elsevier]

We evaluated the genetic and environmental contributions to metabolic cardiovascular risk factors and their mutual associations. Eight metabolic factors (body mass index, waist circumference, waist-to-hip ratio, systolic blood pressure, diastolic blood pressure, total serum cholesterol, serum triglycerides, and serum uric acid) were measured in 508 twin pairs aged 8–17 years from the Qingdao Twin Registry, China. Linear structural equation models were used to estimate the heritability of these traits, as well as the genetic and environmental correlations between them. Among boys, body mass index and uric acid showed consistently high heritability (0.49–0.81), whereas other traits showed moderate to high common environmental variance (0.37–0.73) in children (8–12 years) and adolescents (13–17 years) except total cholesterol. For girls, moderate to high heritability (0.39–0.75) were obtained for six metabolic traits in children, while only two traits showed high heritability and others mostly medium to large common environmental variance in adolescents. Genetic correlations between the traits were strong in both boys and girls in children (rg = 0.64–0.99 between body mass index and diastolic blood pressure; rg = 0.71–1.00 between body mass index and waist circumference), but decreased for adolescent girls (rg = 0.51 between body mass index and waist-to-hip ratio; rg = 0.55 between body mass index and uric acid; rg = 0.61 between body mass index and systolic blood pressure). The effect of genetic factors on most metabolic traits decreased from childhood to adolescence. Both common genetic and specific environmental factors influence the mutual associations among most of the metabolic traits. [ABSTRACT FROM PUBLISHER]

China is facing the great challenge of serving the world's largest rare disease population. It is necessary to develop a specific medical plan to increase the levels of optimal prevention, diagnosis and treatment of rare diseases under the existing clinical service structures in China. In 2013, China launched its first pilot project focused on 20 representative rare diseases. A national network including approximately 100 provincial or municipal medical centers has been established to enable collaboration on rare diseases across China. The main objectives for this project are to develop and apply medical guidelines and clinical pathways for rare diseases, to establish a rare disease patient registry and data repository system, and to promote molecular testing for rare genetic disorders. This project also emphasizes building close links among the collaborative network, clinicians on the frontlines in basic medical services institutions and rare disease patient organizations. Primarily, this project expects to develop an actionable medical services plan to increase the delivery of quality healthcare for individuals and families living with rare diseases in China within five years. [ABSTRACT FROM AUTHOR]

Omenn syndrome (OS) is a rare autosomal recessive genetic disorder and presents symptoms of severe combined immunodeficiency characterized by erythrodermia, eosinophilia, hepatosplenomegaly, lymphadenopathy, and elevated serum IgE levels. OS has been found to be caused by mutations in RAG1 or RAG2 gene that result in partial V(D)J recombination activity. No study on OS has been reported in Chinese children so far. In this study, the genotype and phenotypes of three infants with OS from three unrelated Chinese families were investigated. All the three children had most of the characteristics of OS except normal serum IgE level. Compound heterozygosity mutations in RAG1 gene (1983 G>A; 2444 C>T and 2219 C>T; 3127 C>G) were identified in two cases, and a homozygous deletion mutation with a premature stop codon was found at residue 2302 of RAG1 gene (2302delT, I729X) in the remaining case, including three novel mutations (2302delT, I729X; 2219 C>T, R699W; and 3127 C>G, Y1001X). Spectratyping analysis of T-cell receptor b-chain variable region (TCRVb) gene rearrangement was performed in case 1 and case 2. All the 25 TCRVb subfamilies presented monoclonal or oligoclonal peaks in case 1 and 11 TCRVb subfamilies were very weak or even absent in case 2. This was the first report about OS in Chinese children. Molecular genetic testing represents an important tool for early confirmed diagnosis and may allow accurate carrier detection and prenatal diagnosis. [ABSTRACT FROM AUTHOR]

Schizophrenia is a severe mental disorder with onset frequently in adolescence and followed by a chronic and disabling course. Although the exact pathophysiology of this devastating disorder has not been clearly elucidated, a large part of it has been attributed to genetic influences. This article seeks to provide an overview on what our group has embarked on - to elucidate genetic risk factors for schizophrenia within the Chinese ethnic group. We plan to conduct an integrated approach to interrogate comprehensively the genome from different angles and in stages. The first stage involves a genome-wide association study of 1000 cases of schizophrenia-control pairs, with a follow-up replication study in another 1000 cases of schizophrenia and in 1000 controls, and combination analyses with groups from other places including China and Hong Kong. Other than the genome-wide association study, gene sequencing for purported candidate genes and copy number variation analysis will be performed. Neurocognitive intermediate phenotypes will be employed to deconstruct the complex schizophrenia phenotype in a bid to improve association findings. Promising leads from longitudinal gene and protein expression in ultra-high-risk subjects who develop psychosis and schizophrenia (in a parallel study) will be followed up as candidate genes and sequenced in the genetic analysis. Functional analysis forms the last stage of this integrated approach. This integrated genetic and genomic approach will hopefully help in further characterizing and deepening our understanding of molecular pathophysiological mechanisms underlying schizophrenia. [ABSTRACT FROM AUTHOR]

The article presents a study on the common variations in the BCL9 gene that confer the risk of schizophrenia. The researchers observed stable inpatients or outpatients from a mental health center in Shanghai, China, all of whom were interviewed by two independent psychiatrists. They found that the BCL9 gene is a good candidate for psychiatric diseases because it can be found within a region affected by variations that represent a risk of schizophrenia. They also discussed the psychotic features of schizophrenia including altered cognitive functioning.

Aims To determine the incidence of gestational diabetes mellitus (GDM) in China and to further identify population specific risk factors for GDM. Methods Following a universal GDM screening recommendation, 16 286 pregnant women who underwent a 50-g glucose challenge test from 18 cities in China were followed up through pregnancy. GDM was confirmed by oral glucose tolerance test according to American Diabetes Association criteria. Results The incidence of GDM was 4.3%. Previously reported risk factors for GDM, including advanced maternal age, pre-pregnancy obesity and family history of diabetes, were strongly associated with an elevated GDM risk. Moreover, after the adjustment for the above-mentioned risk factors, a history of recurrent vulvovaginal candidiasis, residency in south China and a history of spontaneous abortion were significantly associated with an increased GDM risk; adjusted odds ratio (OR) [95% confidence interval (95% CI)] were 1.97 (1.39, 2.80), 1.84 (1.59–2.13), and 1.46 (1.12, 1.91), respectively. Conclusions In this large study of GDM in Chinese women, advanced maternal age, pre-pregnancy overweight or obesity and family history of diabetes were confirmed to be risk factors. In addition, a history of recurrent vulvovaginal candidiasis or spontaneous abortion and residency in south China appeared to be novel risk factors in this population. [ABSTRACT FROM AUTHOR]

Background Cleidocranial dysplasia (CCD) is an autosomal-dominant skeletal dysplasia syndrome that is characterized by widely patent calvarial sutures, clavicular hypoplasia, supernumerary teeth, and short stature. It is caused by mutations of the transcription factor RUNX2, which is known as a major regulator of bone differentiation. Objective To report on 3 Chinese pediatric cases of CCD with an emphasis on the clinical presentation and diagnostic modalities. Case Summary 3 Chinese children were admitted to our hospital because of short stature. All the children had hypoplastic clavicles, absent calvarium, open fontanel, and messy palmprint. Screening laboratory test results for bone mineral density, free thyroxine, and thyroid stimulating hormone were all normal. One child had mental retardation. Two were hereditary, and 1 was sporadic. Conclusion These results showed that CCD should be suspected in patients with short stature and poor clavicles, calvarium, or teeth. Timely recognition and hereditary tendency counseling is required and useful. [ABSTRACT FROM AUTHOR]

Abstract: Background: Human bocavirus (HBoV) was first identified in children with acute respiratory-tract infections, but recent studies have revealed that HBoV is also frequently detected in fecal specimens from children with gastroenteritis. Objectives: To investigate the prevalence of HBoV in children hospitalized with gastroenteritis in different areas of China. Study design: Employing ELISA, RT-PCR or PCR, we evaluated 1216 fecal samples for common diarrheal agents from children aged less than 5-year-old hospitalized with acute gastroenteritis. MEGA software was used to construct phylogenetic trees of the VP1/VP2 partial sequences of the HBoV genome. Results: There were 67 HBoV-positive specimens, 52 (77.6%) were co-infected with rotavirus, norovirus, astrovirus, or enteric adenovirus. Statistical analysis of the clinical data indicated that children infected with both rotavirus and bocavirus did not have more severe clinical symptoms than children infected with rotavirus. The phylogenetic analysis of the VP1/VP2 partial sequences of the HBoV genome revealed a single genetic lineage. Conclusions: Despite its high infection rate, there was no statistically significant a causual relationship between HBoV and gastroenteritis in children. [Copyright &y& Elsevier]