Artificial intelligence-based approaches for the detection and prioritization of genomic mutations in congenital surgical diseases.

Genetic mutations are critical factors leading to congenital surgical diseases and can be identified through genomic analysis. Early and accurate identification of genetic mutations underlying these conditions is vital for clinical diagnosis and effective treatment. In recent years, artificial intelligence (AI) has been widely applied for analyzing genomic data in various clinical settings, including congenital surgical diseases. This review paper summarizes current state-of-the-art AI-based approaches used in genomic analysis and highlighted some successful applications that deepen our understanding of the etiology of several congenital surgical diseases. We focus on the AI methods designed for the detection of different variant types and the prioritization of deleterious variants located in different genomic regions, aiming to uncover susceptibility genomic mutations contributed to congenital surgical disorders.

Sequencing of a Chinese tetralogy of Fallot cohort reveals clustering mutations in myogenic heart progenitors.

Tetralogy of Fallot (TOF) is the most common cyanotic heart defect, yet the underlying genetic mechanisms remain poorly understood. Here, we performed whole-genome sequencing analysis on 146 nonsyndromic TOF parent-offspring trios of Chinese ethnicity. Comparison of de novo variants and recessive genotypes of this data set with data from a European cohort identified both overlapping and potentially novel gene loci and revealed differential functional enrichment between cohorts. To assess the impact of these mutations on early cardiac development, we integrated single-cell and spatial transcriptomics of early human heart development with our genetic findings. We discovered that the candidate gene expression was enriched in the myogenic progenitors of the cardiac outflow tract. Moreover, subsets of the candidate genes were found in specific gene coexpression modules along the cardiomyocyte differentiation trajectory. These integrative functional analyses help dissect the pathogenesis of TOF, revealing cellular hotspots in early heart development resulting in cardiac malformations.

Comprehensive genetic testing of Chinese SNHL patients and variants interpretation using ACMG guidelines and ethnically matched normal controls.

Hereditary hearing loss is a monogenic disease with high genetic heterogeneity. Variants in more than 100 deafness genes underlie the basis of its pathogenesis. The aim of this study was to assess the ratio of SNVs in known deafness genes contributing to the etiology of both sporadic and familial sensorineural hearing loss patients from China. DNA samples from 1127 individuals, including normal hearing controls (n = 616), sporadic SNHL patients (n = 433), and deaf individuals (n = 78) from 30 hearing loss pedigrees were collected. The NGS tests included analysis of sequence alterations in 129 genes. The variants were interpreted according to the ACMG/AMP guidelines for genetic hearing loss combined with NGS data from 616 ethnically matched normal hearing adult controls. We identified a positive molecular diagnosis in 226 patients with sporadic SNHL (52.19%) and in patients from 17 deafness pedigrees (56.67%). Ethnically matched MAF filtering reduced the variants of unknown significance by 8.7%, from 6216 to 5675. Some complexities that may restrict causative variant identification are discussed. This report highlight the clinical utility of NGS panels identifying disease-causing variants for the diagnosis of hearing loss and underlines the importance of a broad data of control and ACMG/AMP standards for accurate clinical delineation of VUS variants.

A comparative study on the construction of medical teams in public primary and secondary schools after multi-channel distribution mode in Guangzhou / 中国学校卫生

Objective@#To understand the situation of school medical staff in Guangzhou after adopting multichannel medical model, and to provide reference for school medical team construction.@*Methods@#A total of 1 099 primary and secondary schools in Guangzhou participated in this study through questionnaire survey regarding school medical personnel, basic situation of school medical personnel and work situation.@*Results@#Among the 1 099 primary and secondary schools surveyed, 638(58.05%) of them consisted of 707 full-time school doctors, the eligible rate was 28.20%. The recruitment of school doctors was still based on independent recruitment(55.87%), and 44.13% of the purchase service modes (community deployment, hospital purchase services, and school clinic custody) were deployed. Most of school medical professionals majored in nursing(56.86%), followed by clinical medicine (26.03%) and preventive medicine (9.76%); In terms of professional titles, junior, intermediate and senior certificates accounted for 52.47%, 37.34%, and 1.27%, respectively; More than 68.74% of school doctors worked for less than 5 years; On average, 68.60% of training were provided every six months. About 33.95% of the school doctor were satisfied with salary, 20.79% were not satisfied. Compared with the year 2016, no significant changes were noticed in academic qualifications, professional titles, and working conditions of school medical team, however, increased proportion of staffs with nursing certificate instead of clinical medicine certificate increased, workload and satisfaction towards salary decreased(P<0.01).@*Conclusion@#After adopting the multi-channel deployment model, the construction of school health workforce in Guangzhou has made breakthrough progress. It is proposed to improve the guidelines for the standardization of school doctors, to strengthen the professional skills training of school doctors, and to better improve the overall level of school health work in the city.

Prevalence and impact factors of metabolic disorders among the high school students in Guangzhou / 中国学校卫生

Objective@#To investigate the prevalence of metabolic disorder among the high school students in Guangzhou.@*Methods@#A cross-sectional study among 4 620 high school students selected with stratified cluster sampling was conducted in Guangzhou. Height, weight, blood pressure, fasting plasma glucose (FPG) and serum lipid of TC, TG were measured. Household socioeconomic status, medical history, physical activities as well as personal diet and study habits were acquired with structured questionnaire.@*Results@#The prevalence of central obesity was 11.5%. The overall prevalence of IFG and DM was 6.9%. The overall prevalence of both hypercholesteremia and hypertriglyceridemia was 13.4%. The prevalence of hypertension was 11.6%. With multivariable logistic regression, the results showed that: fast eating was associated with increased risk of central obesity (OR=1.79, 95%CI=1.47-2.18) and hypercholesteremia/hypertriglyceridemia (OR=1.27，95%CI=1.04-1.54). While students who ate slow had low risk of central obesity (OR=0.47, 95%CI=0.33-0.68), hypercholesteremia/hypertriglyceridemia(OR=0.71, 95%CI=0.54-0.94) and hypertension (OR=0.65, 95%CI=0.49-0.88). Students with sugar-sweetened beverages once a day or more had higher risk of central obesity (OR=1.60, 95%CI=1.08-2.38) while students without sugar-sweetened beverages consumption had low risk of IFG/DM (OR=0.57, 95%CI= 0.43-0.77) than those who consumed 1-2 times/week. Students without eating out habit had lower risk of hypercholesteremia /hypertriglyceridemia than those with eating out for 1-2 times/week (OR=0.78, 95%CI=0.62-0.98), and students who had lunch out of home or canteen had higher risk of hypercholesteremia /hypertriglyceridemia than those who ate at canteen (OR=1.38，95%CI=1.06-1.81).@*Conclusion@#The prevalence of metabolic disorder among high school students in Guangzhou is at a relatively high level. High eating speed, heavy sugared beverages intake and frequently eating out habits are associated with risk of metabolic disorder.

Mediation of achievement goal orientation in the association between learning stress and sleep quality among middle school students / 中国学校卫生

Objective@#To explore the associations among achievement goal orientation, learning stress and sleep quality among middle school students.@*Methods@#A total of 5 781 students were recruited from 14 middle schools in Guangzhou by a stratified cluster random sampling method. These students were investigated with learning stressors (SSA), achievement goal orientation (ADG), and Pittsburgh Sleep Quality Index (PSQI).@*Results@#The mean score of four aspects of achievement goal orientation was as follows: performance approach (25.98±6.76), performance avoidance (15.52±4.12), mastery approach (25.87±6.77), mastery avoidance (15.19±4.12). The average score of learning stress and sleep quality was (149.53±42.46) and (6.45±2.86), respectively. Performance approach, mastery avoidance and performance avoidance positively associated with learning stress and sleep quality(r=0.12-0.53, P<0.01). Mastery approach was negatively correlated with learning stress and sleep quality (r=-0.14-0.22, P<0.01). Four types of achievement goal orientation both had a direct effect on sleep quality. Performance avoidance and mastery approach indirectly affected sleep quality through learning stress.@*Conclusion@#Achievement goal orientation of middle school students closely relates to learning stress and sleep quality; performance avoidance and mastery approach indirectly affects sleep quality through learning stress. Positive achievement goal orientation helps to reduce learning stress, which would lead to sleep quality improvement among middle school students.

Further evidence for "gain-of-function" mechanism of DFNA5 related hearing loss.

To report two DFNA5 pathogenic splice-site variations and a novel benign frameshift variation to further support the gain-of-function mechanism of DFNA5 related hearing impairment, targeted genes capture and next generation sequencing were performed on selected members from Family 1007208, 1007081 and a sporadic case with sensorineural hearing loss. Reverse transcriptase polymerase chain reaction was conducted on the proband from Family 1007208 to test how the splice-site variation affects the transcription in RNA level. A novel heterozygous splice-site variation c.991-3 C > A in DFNA5 was found in Family 1007208; a known hotspot heterozygous splice-site variation c.991-15_991_13delTTC was identified in Family 1007081. Both the splice-site variations were segregated with the late onset hearing loss phenotype, leading to the skipping of exon 8 at RNA level. In addition, a novel DFNA5 frameshift variation c.116_119delAAAA was found in the sporadic case, but was not segregated with the hearing impairment phenotype. In conclusion, we identified one novel and one known pathogenic DFNA5 splice-site variation in two Chinese Families, as well as a novel DFNA5 frameshift variation c.116_119delAAAA in a sporadic case, which does not the cause for the hearing loss case. Both the two pathogenic splice-site variations and the nonpathogenic frameshift variation provide further support for the specific gain-of-function mechanism of DFNA5 related hearing loss.

Mutation of IFNLR1, an interferon lambda receptor 1, is associated with autosomal-dominant non-syndromic hearing loss.

Background Hereditary sensorineural hearing loss is a genetically heterogeneous disorder. Objectives This study was designed to explore the genetic etiology of deafness in a large Chinese family with autosomal dominant, nonsyndromic, progressive sensorineural hearing loss (ADNSHL). Methods Whole exome sequencing and linkage analysis were performed to identify pathogenic mutation. Inner ear expression of Ifnlr1 was investigated by immunostaining in mice. ifnlr1 Morpholino knockdown Zebrafish were constructed to explore the deafness mechanism. Results We identified a cosegregating heterozygous missense mutation, c.296G>A (p.Arg99His) in the gene encoding interferon lambda receptor 1 (IFNLR1) - a protein that functions in the Jak/ STAT pathway- are associated with ADNSHL Morpholino knockdown of ifnlr1 leads to a significant decrease in hair cells and non-inflation of the swim bladder in late-stage zebrafish, which can be reversed by injection with normal Zebrafish ifnlr1 mRNA. Knockdown of ifnlr1 in zebrafish causes significant upregulation of cytokine receptor family member b4 (interleukin-10r2), jak1, tyrosine kinase 2, stat3, and stat5b in the Jak1/STAT3 pathway at the mRNA level. ConclusionIFNLR1 function is required in the auditory system and that IFNLR1 mutations are associated with ADNSHL. To the best of our knowledge, this is the first study implicating an interferon lambda receptor in auditory function.

Identification of a missense HOXD13 mutation in a Chinese family with syndactyly type I-c using exome sequencing.

Syndactyly is one of the most common hereditary limb malformations, and is characterized by the fusion of specific fingers and/or toes. Syndactyly type I­c is associated with bilateral cutaneous or bony webbing of the third and fourth fingers and occasionally of the third to fifth fingers, with normal feet. The aim of the present study was to identify the genetic basis of syndactyly type I­c in four generations of a Chinese Han family by exome sequencing. Exome sequencing was conducted in the proband of the family, followed by direct sequencing of other family members of the same ancestry, as well as 100 ethnically­matched, unrelated normal controls. A missense mutation, c.917G>A (p.R306Q), was identified in the homeobox D13 gene (HOXD13). Sanger sequencing verified the presence of this mutation in all of the affected family members. By contrast, this mutation was absent in the unaffected family members and the 100 ethnically­matched normal controls. The results suggest that the c.917G>A (p.R306Q) mutation in the HOXD13 gene, may be responsible for syndactyly type I­c in this family. Exome sequencing may therefore be a powerful tool for identifying mutations associated with syndactyly, which is a disorder with high genetic and clinical heterogeneity. The results provide novel insights into the etiology and diagnosis of syndactyly, and may influence genetic counseling and the clinical management of the disease.

Clinical Auditory Phenotypes Associated with GATA3 Gene Mutations in Familial Hypoparathyroidism-deafness-renal Dysplasia Syndrome.

BACKGROUND: Hypoparathyroidism-deafness-renal dysplasia (HDR) syndrome is an autosomal dominant disorder primarily caused by haploinsufficiency of GATA binding protein 3 (GATA3) gene mutations, and hearing loss is the most frequent phenotypic feature. This study aimed at identifying the causative gene mutation for a three-generation Chinese family with HDR syndrome and analyzing auditory phenotypes in all familial HDR syndrome cases. METHODS: Three affected family members underwent otologic examinations, biochemistry tests, and other clinical evaluations. Targeted genes capture combining next-generation sequencing was performed within the family. Sanger sequencing was used to confirm the causative mutation. The auditory phenotypes of all reported familial HDR syndrome cases analyzed were provided. RESULTS: In Chinese family 7121, a heterozygous nonsense mutation c.826C>T (p.R276*) was identified in GATA3. All the three affected members suffered from sensorineural deafness and hypocalcemia; however, renal dysplasia only appeared in the youngest patient. Furthermore, an overview of thirty HDR syndrome families with corresponding GATA3 mutations revealed that hearing impairment occurred earlier in the younger generation in at least nine familial cases (30%) and two thirds of them were found to carry premature stop mutations. CONCLUSIONS: This study highlights the phenotypic heterogeneity of HDR and points to a possible genetic anticipation in patients with HDR, which needs to be further investigated.

Whole Exome Sequencing Identifies a Novel Mutation in the PITX3 Gene, Causing Autosomal Dominant Congenital Cataracts in a Chinese Family.

BACKGROUND: Congenital cataract is the cloudiness of the eye's natural lens and is a primary cause of congenital vision loss. It accounts for almost 10% of childhood vision loss worldwide. METHODS: A four generation Chinese family having seven affected individuals was recruited for the current study. Exome sequencing was performed to identify the genetic cause of congenital cataract. RESULTS: Analysis of data identified a novel frameshift mutation, c.608delC (p.A203fs), in the PITX3 gene. This mutation was only observed in the affected individuals while the unaffected members of the family as well as 100 ethnically matched normal controls did not contain this deletion. CONCLUSION: These findings suggest that p.A203fs is the cause of cataracts in the recruited family. This information would be further helpful in the genetic diagnosis of cataract and in the genetic counseling of similar patients.

Compound heterozygous POMT1 mutations in a Chinese family with autosomal recessive muscular dystrophy-dystroglycanopathy C1.

Muscular dystrophy-dystroglycanopathy (MDDG) is a genetically and clinically heterogeneous group of muscular disorders, characterized by congenital muscular dystrophy or later-onset limb-girdle muscular dystrophy accompanied by brain and ocular abnormalities, resulting from aberrant alpha-dystroglycan glycosylation. Exome sequencing and Sanger sequencing were performed on a six-generation consanguineous Han Chinese family, members of which had autosomal recessive MDDG. Compound heterozygous mutations, c.1338+1G>A (p.H415Kfs*3) and c.1457G>C (p.W486S, rs746849558), in the protein O-mannosyltransferase 1 gene (POMT1), were identified as the genetic cause. Patients that exhibited milder MDDG manifested as later-onset progressive proximal pelvic, shoulder girdle and limb muscle weakness, joint contractures, mental retardation and elevated creatine kinase, without structural brain or ocular abnormalities, were further genetically diagnosed as MDDGC1. The POMT1 gene splice-site mutation (c.1338+1G>A) which leads to exon 13 skipping and results in a truncated protein may contribute to a severe phenotype, while the allelic missense mutation (p.W486S) may reduce MDDG severity. These findings may expand phenotype and mutation spectrum of the POMT1 gene. Clinical diagnosis supplemented with molecular screening may result in more accurate diagnoses of, prognoses for, and improved genetic counselling for this disease.

Identification of a Novel Missense FBN2 Mutation in a Chinese Family with Congenital Contractural Arachnodactyly Using Exome Sequencing.

Congenital contractural arachnodactyly (CCA, OMIM 121050), also known as Beals-Hecht syndrome, is an autosomal dominant disorder of connective tissue. CCA is characterized by arachnodactyly, dolichostenomelia, pectus deformities, kyphoscoliosis, congenital contractures and a crumpled appearance of the helix of the ear. The aim of this study is to identify the genetic cause of a 4-generation Chinese family of Tujia ethnicity with congenital contractural arachnodactyly by exome sequencing. The clinical features of patients in this family are consistent with CCA. A novel missense mutation, c.3769T>C (p.C1257R), in the fibrillin 2 gene (FBN2) was identified responsible for the genetic cause of our family with CCA. The p.C1257R mutation occurs in the 19th calcium-binding epidermal growth factor-like (cbEGF) domain. The amino acid residue cysteine in this domain is conserved among different species. Our findings suggest that exome sequencing is a powerful tool to discover mutation(s) in CCA. Our results may also provide new insights into the cause and diagnosis of CCA, and may have implications for genetic counseling and clinical management.