Publications by authors named "Ruen Yao"

40 Publications

Clinical characteristics and survival of children with hypertrophic cardiomyopathy in China: A multicentre retrospective cohort study.

EClinicalMedicine 2022 Jul 27;49:101466. Epub 2022 May 27.

Department of Cardiology, Shanghai Children's Medical Centre, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.

Background: Few data on paediatric hypertrophic cardiomyopathy (HCM) are available in developing countries. A multicentre, retrospective, cohort study was conducted to profile the clinical characteristics and survival of children with HCM in China.

Methods: We collected longitudinal data on children with HCM aged 0-18 years at three participating institutions between January 1, 2010 and December 31, 2019. Patients were identified by searching for the diagnosis using ICD-10 codes from the electronic medical records database. HCM was diagnosed morphologically with echocardiography or cardiovascular magnetic resonance imaging. The exclusion criteria were secondary aetiologies of myocardial hypertrophy. The primary outcomes were all-cause death or heart transplantation. The Kaplan-Meier method was used to estimate the survival rate of different groups.

Findings: A total of 564 children were recruited, with a median age at diagnosis of 1.0 year (interquartile range, IQR: 0.4-8.0 years), followed for a median of 2.6 years (1977 patient-years, IQR:0.5, 5.9 years). The underlying aetiology was sarcomeric (382, 67.7%), inborn errors of metabolism (IEMs) (108, 19.2%), and RASopathies (74, 13.1%). A total of 149 patients (26.4%) died and no patients underwent heart transplantation during follow-up. The survival probability was 71.1% (95% confidence interval [CI], 66.3%-75.3%) at 5 years. Patients with IEMs or those diagnosed during infancy had the poorest outcomes, with an estimated 5-year survival rate of 16.9% (95% CI, 7.7%-29.1%) and 56.0% (95% CI, 48.8%-62.5%), respectively. Heart failure was the leading cause of death in the cohort (90/149, 60.4%), while sudden cardiac death was the leading cause in patients with sarcomeric HCM (32/66, 48.5%).

Interpretation: There is a high proportion of patients with IEM and a low proportion of patients with neuromuscular disease in children with HCM in China. Overall, mortality remains high in China, especially in patients with IEMs and those diagnosed during infancy.

Funding: National Natural Science Fund of China (81770380, 81974029), China Project of Shanghai Municipal Science and Technology Commission (20MC1920400, 21Y31900301).
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http://dx.doi.org/10.1016/j.eclinm.2022.101466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9157015PMC
July 2022

Study of novel variants in patient of combined oxidative phosphorylation deficiency 24.

Transl Pediatr 2022 Apr;11(4):448-457

Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Background: catalyzes the attachment of asparagine amino acids to mitochondrial tRNA and is critical for efficient mitochondrial protein synthesis. Biallelic variants in are associated with combined oxidative phosphorylation deficiency 24 (COXPD24) and autosomal recessive deafness-94.

Methods: Patient information was obtained after recruitment. Genetic tests were performed using whole exome sequencing (WES) and Sanger sequencing. Structure prediction was based on the RaptorX and SWISS-MODEL platforms. The mRNA analysis of paternal variant was performed. Expression levels and dimerization of wild-type (WT) and mutant were detected in human embryonic kidney (HEK) 293T cells. Mitochondrial localization of variants was determined using immunofluorescence staining.

Results: The patient presented early onset generalized epilepsy, myoclonic seizures, severe bilateral hearing impairment and affected liver and heart. WES identified two compound heterozygous variants in : c.1141A>G/p.Asn381Asp and c.1290G>C/p.Trp430Cys. In silico analysis predicted that both variants would cause significant and pathogenic changes in secondary structure. c.1290G>C is a variant at the first nucleotide of an exon, a location thought to affect mRNA splicing. Although transcriptional experiments did not identify aberrant splicing, we observed a lower proportion of transcripts from the 2 c.1290G>C variant. An experiment showed that both variants impaired expression, while mitochondrial localization and dimerization remained unaffected.

Conclusions: The patient was diagnosed with COXPD24 caused by novel variations. The cardiac dysfunction is identified for the first time. study revealed impairment of variants on expression. These data enrich our knowledge regarding the phenotypic and genotypic spectra of .
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http://dx.doi.org/10.21037/tp-21-570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9085945PMC
April 2022

Novel RARS2 Variants: Updating the Diagnosis and Pathogenesis of Pontocerebellar Hypoplasia Type 6.

Pediatr Neurol 2022 06 15;131:30-41. Epub 2022 Apr 15.

Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China. Electronic address:

Background: Pontocerebellar hypoplasia type 6 (PCH6) is an early-onset encephalopathy with/without mitochondrial respiratory complex defects caused by recessive mutations in mitochondrial arginyl-tRNA synthetase (RARS2). Highly heterogeneous clinical phenotypes and numerous missense variations of uncertain significance make diagnosis difficult. Pathogenesis of PCH6 remains unclear.

Methods: Facial characteristics of patients were assessed. Genetic tests were performed. Structure prediction was based on the template from AlphaFold Protein Structure Database. Expression of mutant RARS2 was tested in HEK293T cells. Patient-derived induced pluripotent stem cells (iPSCs) were detected for human mitochondrial tRNA (hmtRNA) steady-state level, mitochondrial respiratory complex (MRC) activity, oxygen consumption rate (OCR), extracellular acidification rate (ECAR), mitochondrial membrane potential (MMP), reactive oxygen species (ROS) abundance, and apoptosis level.

Results: The three pedigrees were diagnosed as PCH6 caused by compound heterozygous RARS2 variations. Five RARS2 variants were identified: c.3G>C(p.M1?), c.685C>T(p.R229∗), c.1060T>A(p.F354I), c.1210A>G(p.M404V), and c.1369G>A(p.G457R). RARS2 c.3G>C disrupted protein expression. RARS2 c.685C>T created a truncated protein lacking complete catalytic core and anticodon-binding domain. RARS2 c.1060T>A and c.1369G>A were predicted to cause structural abnormality. The hmtRNA steady-state abundance in a patient's iPSCs was unaffected. Mitochondrial energy metabolism was normal, including MRC activity, OCR, ECAR, and MMP, while mitochondria-related cellular characteristics, including ROS (P < 0.001) and apoptosis levels (P < 0.001), increased.

Conclusions: This study reports five RARS2 variations among which c.3G>C and c.1060T>A are novel. Summarized facial features of PCH6 patients will facilitate diagnosis. Defective mitochondrial energy metabolism may not be key points, but mitochondria-related abnormal cellular physiology, including apoptosis, may be an underlying pathogenesis.
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http://dx.doi.org/10.1016/j.pediatrneurol.2022.04.002DOI Listing
June 2022

Case Report: A Relatively Mild Phenotype Produced by Novel Mutations in the Gene.

Front Pediatr 2021 26;9:805575. Epub 2022 Jan 26.

Department of Developmental and Behavioral Pediatrics, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Mutations in the human -phosphoseryl-tRNA:selenocysteinyl-tRNA synthase gene ( are associated with progressive cerebello-cerebral atrophy (PCCA), also known as pontocerebellar hypoplasia type 2D (PCH2D). Early-onset profound developmental delay, progressive microcephaly, and hypotonia that develops toward severe spasticity have been previously reported with mutations. Herein we report a case with severe global developmental delay, myogenic changes in the lower limbs, and insomnia, but without progressive microcephaly and brain atrophy during infancy and toddlerhood in a child harboring the missense variant c.194A>G (p. Asn65Ser) and a novel splicing mutation c.701+1G>A. With these findings we communicate the first Chinese mutant case, and our report indicates that mutations can give rise to a milder phenotype.
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http://dx.doi.org/10.3389/fped.2021.805575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8826681PMC
January 2022

Genetic Diagnosis Spectrum and Multigenic Burden of Exome-Level Rare Variants in a Childhood Epilepsy Cohort.

Front Genet 2021 21;12:782419. Epub 2021 Dec 21.

Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Childhood epilepsy is a considerably heterogeneous neurological condition with a high worldwide incidence. Genetic diagnosis of childhood epilepsy provides the most accurate pathogenetic evidence; however, a large proportion of highly suspected cases remain undiagnosed. Accumulation of rare variants at the exome level as a multigenic burden contributing to childhood epilepsy should be further evaluated. In this retrospective analysis, exome-level sequencing was used to depict the mutation spectra of 294 childhood epilepsy patients from Shanghai Children's Medical Center, Department of Neurology. Furthermore, variant information from exome sequencing data was analyzed apart from monogenic diagnostic purposes to elucidate the possible multigenic burden of rare variants related to epilepsy pathogenesis. Exome sequencing reached a diagnostic rate of 30.61% and identified six genes not currently listed in the epilepsy-associated gene list. A multigenic burden study revealed a three-fold possibility that deleterious missense mutations in ion channel and synaptic genes in the undiagnosed cohort may contribute to the genetic risk of childhood epilepsy, whereas variants in the gene categories of cell growth, metabolic, and regulatory function showed no significant difference. Our study provides a comprehensive overview of the genetic diagnosis of a Chinese childhood epilepsy cohort and provides novel insights into the genetic background of these patients. Harmful missense mutations in genes related to ion channels and synapses are most likely to produce a multigenic burden in childhood epilepsy.
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http://dx.doi.org/10.3389/fgene.2021.782419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8725238PMC
December 2021

Clinical Profiles and Genetic Spectra of 814 Chinese Children With Short Stature.

J Clin Endocrinol Metab 2022 03;107(4):972-985

Department of Endocrinology and Metabolism, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Context: Data and studies based on exome sequencing for the genetic evaluation of short stature are limited, and more large-scale studies are warranted. Some factors increase the likelihood of a monogenic cause of short stature, including skeletal dysplasia, severe short stature, and small for gestational age (SGA) without catch-up growth. However, whether these factors can serve as predictors of molecular diagnosis remains unknown.

Objective: We aimed to explore the diagnostic efficiency of the associated risk factors and their exome sequences for screening.

Methods: We defined and applied factors that increased the likelihood of monogenic causes of short stature in diagnostic genetic tests based on next-generation sequencing (NGS) in 814 patients with short stature and at least 1 other factor.

Results: Pathogenic/likely pathogenic (P/LP) variants in genes, copy number variations, and chromosomal abnormalities were identified in 361 patients. We found P/LP variants among 111 genes, and RASopathies comprised the most important etiology. Short stature combined with other phenotypes significantly increased the likelihood of a monogenic cause, including skeletal dysplasia, facial dysmorphism, and intellectual disability, compared with simple severe short stature (<-3 SD scores). We report novel candidate pathogenic genes, KMT2C for unequivocal growth hormone insensitivity and GATA6 for SGA.

Conclusion: Our study identified the diagnostic characteristics of NGS in short stature with different risk factors. Our study provides novel insights into the current understanding of the etiology of short stature in patients with different phenotypes.
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http://dx.doi.org/10.1210/clinem/dgab863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8947318PMC
March 2022

Novel truncating variant of MN1 penultimate exon identified in a Chinese patient with newly recognized MN1 C-terminal truncation syndrome: Case report and literature review.

Int J Dev Neurosci 2022 Feb 4;82(1):96-103. Epub 2021 Nov 4.

Department of Rehabilitation Medicine, Children's Hospital of Soochow University, Suzhou, China.

MN1 C-terminal truncation (MCTT) syndrome is a newly recognized neurodevelopmental disorder due to heterozygous gain-of-function C-terminal truncating mutations clustering in the last or penultimate exon of MN1 gene (MIM: 156100). Up to date, only 25 affected patients have been reported. Here, we report a 2-year-old Chinese girl with MCTT syndrome. The girl presented with the characteristic features of the syndrome, including global developmental delay (GDD), facial dysmorphism and hearing impairment. Notably, the patient did not have other frequently observed symptoms such as hypotonia, cranial or brain abnormalities, indicating variability of the phenotype of patients with MN1 C-terminal truncating mutations. Trio whole-exome sequencing revealed a novel de novo heterozygous nonsense variant in the extreme 3' region of penultimate exon of MN1 (NM_002430.3: c.3743G > A, p.Trp1248*). This rare truncating variant was classified as pathogenic due to its predicted gain-of-function effect, given that the gain-of-function MN1 truncating variants producing C-terminally truncated proteins have been confirmed to cause the recognizable syndrome. Additionally, a systematic review of previously reported MN1 variants including C-terminal truncating variants and N-terminal truncating variants shows that different location of MN1 truncating variants causes two distinct clinical subtypes. To our knowledge, this is the first reported case of MCTT syndrome caused by a novel MN1 C-terminal truncating variant in a Chinese population, which enriched the mutation spectrum of MN1 gene and further supporting the association of the novel MCTT syndrome with MN1 C-terminal truncating variants.
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http://dx.doi.org/10.1002/jdn.10154DOI Listing
February 2022

Genetic and Phenotypic Characteristics of Congenital Hypothyroidism in a Chinese Cohort.

Front Endocrinol (Lausanne) 2021 3;12:705773. Epub 2021 Sep 3.

Department of Pediatrics, Affiliated Changzhou Children's Hospital of Nantong University, Changzhou, China.

Background: The molecular etiology and the genotype-phenotype correlation of congenital hypothyroidism (CH) remain unclear.

Methods: We performed genetic analysis in 42 newborns with CH using whole-exome sequencing. Patients were divided into a single-gene group and a multi-gene group according to the number of affected genes, or divided into a monoallelic group, a biallelic group, and an oligogenic group according to the pattern of the detected variants. The clinical characteristics were compared between groups.

Results: Thyroid dysgenesis (TD) was observed in 10 patients and goiter in 5 patients, whereas 27 patients had normal-sized gland-in-situ (GIS). We identified 58 variants in five genes in 29 patients. The genes with the most frequent variants were (70.7%), followed by (12.1%), (10.3%), and (5.2%). Variants in the genes causing dyshormonogenesis (DH) were more common than those in the genes causing TD (87.9% 12.1%). Among the patients with detected variants, 26 (89.7%) were harboring a single gene variant (single-gene group), which include 22 patients harboring biallelic variants (biallelic group) and four patients harboring monoallelic variants (monoallelic group). Three (10.3%) patients harbored variants in two or three genes (multi-gene group or oligogenic group). Compared with the single-gene group, the levothyroxine (L-T4) dose at 1 year of age was higher in the multi-gene group ( = 0.018). A controllable reduction in the L-T4 dose was observed in 25% of patients in the monoallelic group and 59.1% of patients in the biallelic group; however, no patients with such reduction in the L-T4 dose were observed in the oligogenic group.

Conclusions: Patients with normal-sized GIS accounted for the majority of our cohort. Genetic defects in the genes causing DH were more common than those in the genes causing TD, with biallelic variants in being dominant. DH might be the leading pathophysiology of CH in Chinese individuals.
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http://dx.doi.org/10.3389/fendo.2021.705773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8446595PMC
February 2022

Trio exome sequencing identified a novel de novo WASF1 missense variant leading to recurrent site substitution in a Chinese patient with developmental delay, microcephaly, and early-onset seizures: A mutational hotspot p.Trp161 and literature review.

Clin Chim Acta 2021 Dec 31;523:10-18. Epub 2021 Aug 31.

Department of Neurology, Children's Hospital of Soochow University, 92 Zhongnan Street, Suzhou Industrial Park, Suzhou 215025, Jiangsu, China. Electronic address:

Background: Neurodevelopmental disorder with absent language and variable seizures (NEDALVS, OMIM # 618707) is a newly described autosomal dominant condition caused by heterozygous de novo mutation in WASF1 gene. WASF1 is a key component of the WAVE regulatory complex (WRC) required for actin polymerization. So far, only 3 distinct truncating variants clustering at the WCA domain, 3 missense variants localized to the meander region and a copy number variant (CNV) of WASF1 have been identified among 11 NEDALVS cases previously reported.

Case Report: We report a pediatric patient carrying novel de novo heterozygous missense variant (NM_003931.2: c.481T > C, p.Trp161Arg) in WASF1 gene. During the first hospitalization at age of 5.5 months, the patient was initially diagnosed with infantile spasms, developmental delay (DD) and microcephaly due to nodding-like epileptic spasms in clusters and hypsarrhythmia on video-electroencephalography, lacking head control and body rollover, and abnormal head circumference 39 cm (<-2SD). The genetic diagnosis with a causal WASF1 variant detected by trio exome sequencing indicated the rare NEDALVS.

Literature Review: All the reported NEDALVS cases published in the PubMed English literature were reviewed to summarize the genetic and phenotypic spectrum of this novel disorder.

Conclusion: We describe the third patient with a recurrently mutated amino acid site at p.Trp161 in WASF1, currently the 12th patient with NEDALVS. This hotspot missense variant and the truncating variants in WASF1 lead to similar phenotypic patterns with core features of severe DD/ID, and seizures, hypotonia, and microcephaly frequently observed. Our finding expands the WASF1 mutation spectrum and confirms the de novo hotspot missense variant at p.Trp161, further supporting the association of the novel NEDALVS with WASF1 gene and the actin regulatory pathway.
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http://dx.doi.org/10.1016/j.cca.2021.08.030DOI Listing
December 2021

Identification of SOFT syndrome caused by a pathogenic homozygous splicing variant of POC1A: a case report.

BMC Med Genomics 2021 08 21;14(1):207. Epub 2021 Aug 21.

Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China.

Background: Pathogenic variants in POC1A led to SOFT syndrome and variant POC1A-related (vPOC1A) syndrome. SOFT syndrome is a rare primordial dwarfism condition characterized by short stature, onychodysplasia, facial dysmorphism and hypotrichosis.The main clinical differences between SOFT and vPOC1A syndrome include dyslipidemia with insulin resistance and acanthosis nigricans. To our knowledge, this is the first report of a SOFT syndrome patient diagnosed with a homozygous splicing variant, which could help to extend our understanding of the genotypic and phenotypic information of the disease.

Case Presentation: We reported a seven-year-old boy with SOFT syndrome. The patient presented symmetrical short stature and facial features, including prominent forehead, inverted triangular face, epicanthal fold, small teeth and enlarged ears. Laboratory tests displayed mild insulin resistance. Whole-exome sequencing (WES) led to the identification of a homozygous splicing variant (c.981+1G>A) in POC1A gene of the patient, which was inherited from his heterozygous parents confirmed by Sanger sequencing. Further transcriptional experiments of the splicing variant revealed aberrant percentage of exon 9 skipping transcripts.

Conclusions: This is the firstly reported case of a SOFT syndrome patient with a novel homozygous splicing variant and detailed delineation of the aberrant transcript in proband and carrier of the variant in Chinese. Our study enriched mutational spectrum of POC1A which could help in further genetic diagnosis and counselling of SOFT syndrome patients.
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http://dx.doi.org/10.1186/s12920-021-01055-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379828PMC
August 2021

A novel homozygous variant of COL2A1 in a Chinese male with type II collagenopathy: a case report.

BMC Med Genomics 2021 08 11;14(1):201. Epub 2021 Aug 11.

Department of Endocrinology, Genetics and Metabolism, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Background: Type II collagenopathies are a spectrum of diseases and skeletal dysplasia is one of the prominent features of collagenopathies. Molecular defects of the COL2A1 gene cause type II collagenopathies that is mainly an autosomal dominant disease, whereas some rare cases with autosomal recessive inheritance of mode have also been identified.

Case Presentation: The patient was a 5-year-old male with a short neck, flat face, epiphyseal dysplasia, irregular vertebral endplates, and osteochondritis. Sequencing result indicated NM_001844.4: c.3662C > T; p. (Ser1221Phe) a novel missense variant, leading to a serine-to-phenylalanine substitution. Sanger sequencing confirmed the variant compared to his parents and brother.

Conclusions: We identified a novel homozygous variant of the COL2A1 gene as the cause of type II collagenopathies in a Chinese male, enriching the spectrum of genotypes. This is the first case of type II collagenopathies inherited in an autosomal recessive manner in China and East Asia, and it is the first case that resulted from serine substitution in the world.
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http://dx.doi.org/10.1186/s12920-021-01048-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359039PMC
August 2021

Value of Exome Sequencing in Diagnosis and Management of Recurrent Non-immune Hydrops Fetalis: A Retrospective Analysis.

Front Genet 2021 9;12:616392. Epub 2021 Apr 9.

Department of Fetal Medicine, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.

The purpose of the study was to use exome sequencing (ES) to study the contribution of single-gene disorders to recurrent non-immune hydrops fetalis (NIHF) and retrospectively evaluate the value of genetic diagnosis on prenatal management and pregnancy outcome. From January 2012 to October 2018, a cohort of 28 fetuses with recurrent NIHF was analyzed by trio ES. Fetuses with immune hydrops, non-genetic factors (including infection, etc.), karyotype, or CNV abnormalities were excluded. Variants were interpreted based on ACMG/AMP guidelines. Fetal therapy was performed on seven fetuses. Of the 28 fetuses, 10 (36%) were found to carry causal genetic variants (pathogenic or likely pathogenic) in eight genes (, , , , , , , and ). Five (18%) fetuses had variant(s) of uncertain significance (VUS). Of the 10 fetuses with definitive molecular diagnosis, five (50%) were diagnosed with inborn errors of metabolism. Among the seven fetuses who received fetal therapy, two had definitive molecular diagnosis and resulted in neonatal death. Among the remaining five fetuses with negative results, four had newborn survival and one had intrauterine fetal death. Trio ES could facilitate genetic diagnosis of recurrent NIHF and improve the prenatal management and pregnancy outcome.
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http://dx.doi.org/10.3389/fgene.2021.616392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063045PMC
April 2021

CNV profiles of Chinese pediatric patients with developmental disorders.

Genet Med 2021 04 5;23(4):669-678. Epub 2021 Jan 5.

Key Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproduction, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Purpose: To examine the overall genomic copy-number variant (CNV) landscape of Chinese pediatric patients with developmental disorders.

Methods: De-identified chromosomal microarray (CMA) data from 10,026 pediatric patients with developmental disorders were collected for re-evaluating the pathogenic CNV (pCNV) yields of different medical conditions and for comparing the frequency and phenotypic variability of genomic disorders between the Chinese and Western patient populations.

Results: The overall yield of pCNVs in the Chinese pediatric patient cohort was 21.37%, with variable yields for different disorders. Yields of pCNVs were positively associated with phenotypic complexity and intellectual disability/developmental delay (ID/DD) comorbidity for most disorders. The genomic burden and pCNV yield in neurodevelopmental disorders supported a female protective effect. However, the stratification analysis revealed that it was seen only in nonsyndromic ID/DD, not in nonsyndromic autism spectrum disorders or seizure. Furthermore, 15 known genomic disorders showed significantly different frequencies in Chinese and Western patient cohorts, and profiles of referred clinical features for 15 known genomic disorders were also significantly different in the two cohorts.

Conclusion: We defined the pCNV yields and profiles of the Chinese pediatric patients with different medical conditions and uncovered differences in the frequency and phenotypic diversity of genomic disorders between Chinese and Western patients.
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http://dx.doi.org/10.1038/s41436-020-01048-yDOI Listing
April 2021

Novel variants in CIITA caused type II bare lymphocyte syndrome: A case report.

Asian Pac J Allergy Immunol 2021 Jan 2. Epub 2021 Jan 2.

Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.

Background: Type II bare lymphocyte syndrome (BLS II) group A is a rare primary severe immunodeficiency caused by defects in CIITA, one of genes encoding transcriptional regulatory factors for MHC II molecules.

Objective: To report a Chinese boy with mutation of CIITA.

Methods: By reviewing the clinical data of the child and performing a literature search of BLS II group A.

Results: The patient was presented with persistent pneumonia, chronic diarrhea, urinary tract infection, rash, failure to thrive and special facial characteristics. The patient carried novel mutations in CIITA (c.1243delC, p.R415fs*2 and c.3226C>T, p.R1076W) which were identified by next-generation sequencing and confirmed by Sanger sequencing.

Conclusions: This study found novel mutations in the CIITA gene of BLS II, which complemented the mutation spectrum and contributed to the diagnosis, treatment, genetic counseling and prenatal diagnosis of BLS II.
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http://dx.doi.org/10.12932/AP-020720-0898DOI Listing
January 2021

Psychomotor development and attention problems caused by a splicing variant of CNKSR2.

BMC Med Genomics 2020 12 9;13(1):182. Epub 2020 Dec 9.

Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, People's Republic of China.

Background: Mutations in CNKSR2 have been described in patients with neurodevelopmental disorders characterized by childhood epilepsy, language deficits, and attention problems. The encoded protein plays an important role in synaptic function.

Case Presentation: Whole-exome sequencing was applied to detect pathogenic variants in a patient with clinical symptoms of psychomotor development, attention deficit, poor logical thinking ability, and an introverted personality, but without epilepsy or any significant electroencephalogram changes. Genetic study revealed a splicing mutation (c.1904 + 1G > A) and RT-PCR revealed aberrant splicing of exon 16, leading to a reading-frame shift and a truncated protein in the PH domain.

Conclusions: This is the first report of a splicing variant of CNKSR2, and the unique clinical features of this pedigree will help extend our understanding of the genetic and phenotypic spectra of CNKSR2-related disorders.
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http://dx.doi.org/10.1186/s12920-020-00844-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727132PMC
December 2020

TRPS1 mutation detection in Chinese patients with Tricho-rhino-phalangeal syndrome and identification of four novel mutations.

Mol Genet Genomic Med 2020 10 10;8(10):e1417. Epub 2020 Aug 10.

Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.

Background: Tricho-rhino-phalangeal syndrome (TRPS) is a rare autosomal dominant disorder characterized by craniofacial and skeletal malformations including short stature, thin scalp hair, sparse lateral eyebrows, a pear-shaped nose, and cone-shaped epiphyses. This condition is caused by haploinsufficiency or dominant-negative effect of the TRPS1 gene.

Methods: In this study, we analyzed the clinical and genetic data of five unrelated TRPS patients. They were suspected of having TRPS on the basis of clinical and radiological features including typical hair and facial features, as well as varying degrees of skeletal abnormalities. Next-generation sequencing was performed to identify variants of the TRPS1 gene in the five patients.

Results: In patient 1, we found a novel mutation at c.1338C>A (p.Tyr446*) (de novo). Patient 2 had a novel phenotype of hydrocephaly and Arnold-Chiari syndrome and we also found a maternally inherited novel mutation at c.2657C>A (p.Ser886*). Patient 3 had a de novo novel mutation at c.2726G>C (p.Cys909Ser) leading to more severe phenotypes. Patient 4 had a paternally inherited known mutation at c.2762G>A (p.Arg921Gln). Patient 5 with a novel phenotype of hepatopathy had a novel deletion at [GRCh37] del(8)(q23.3-q24.11) chr8:g.116,420,724-119,124,058 (over 2,700 kb). In addition, the patient 3 who harboring missense variants in the GATA binding domain of TRPS1 showed more severe craniofacial and skeletal phenotypes.

Conclusions: We describe four novel mutations and two novel phenotypes in five patients. The mutational and phenotypic spectrum of TRPS is broadened by our study on TRPS mutations. Our results reveal the significance of molecular analysis of TRPS1 for improving the clinical diagnosis of TRPS.
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http://dx.doi.org/10.1002/mgg3.1417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549555PMC
October 2020

Further delineation of bone marrow failure syndrome caused by novel compound heterozygous variants of MYSM1.

Gene 2020 Oct 5;757:144938. Epub 2020 Jul 5.

Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China; Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China. Electronic address:

Myb-like SWIRM and MPN domains (MYSM1) is a chromatin-binding transcriptional regulator that mediates histone 2A deubiquitination, which plays a vital role in hematopoiesis and lymphocyte differentiation. Biallelic variants in MYSM1 cause a rare bone marrow failure syndrome (OMIM #618116). To date, only three pathogenic variants (E390*, R478*, and H656R) of MYSM1 have been reported in nine patients, and all variants are homozygous. Here, we describe a Chinese female patient who mainly presented with leukopenia, granulocytopenia, thrombocytopenia, severe anemia, and B-cell and natural killer cell deficiency in the peripheral blood, and was diagnosed with bone marrow failure. Trio whole-exome sequencing revealed a novel compound heterozygous variant in MYSM1 (c.399G > A, p.L133L, and c.1467C > G, p.Y489*). The c.399G > A synonymous variant is located at the 3'-end of exon 6, which is predicted to affect MYSM1 mRNA splicing. Analysis of the products obtained from the reverse transcription-polymerase chain reaction revealed that the c.399G > A variant leads to exon 6 skipping, resulting in a premature termination codon (c.321_399 del, p.V108Lfs*13). cDNA sequencing suggested that the c.1467C > G variant triggered nonsense-mediated mRNA degradation. Moreover, we identified a novel transcript of MYSM1 mRNA (missing exons 5 and 6) in human blood cells. Our results expand the mutation spectrum of MYSM1; additionally, this is the first report of a synonymous splicing variant that induces post-transcriptional skipping of exon 6 leading to a bone marrow failure syndrome phenotype.
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http://dx.doi.org/10.1016/j.gene.2020.144938DOI Listing
October 2020

Further delineation of primary B cell immunodeficiency caused by novel variants of the BLNK gene in two Chinese patients.

Clin Immunol 2020 05 16;214:108387. Epub 2020 Mar 16.

Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China. Electronic address:

Biallelic variants in BLNK cause primary B-cell immunodeficiency that usually results in absence of B cells and immunoglobulin. Here, we identified disease-causing variant(s) in two unrelated Chinese patients with agammaglobulinemia. Patient 1 showed a moderate reduction in total B-cell count but demonstrated both extremely low levels of memory B-cells and lower levels of memory T cells relative to those in healthy controls. Whole-exome sequencing (WES) revealed a novel heterozygous splice variant (c.676+1G>A), and suggested exon 9 deletion from BLNK, which was subsequently validated by quantitative polymerase chain reaction. For Patient 2, WES revealed novel compound heterozygous of a frameshift variant (p.T152Pfs*6) and a synonymous variant (c.525G>A) that resulted in exon 6 skipping, according to cDNA sequencing. These findings represent the first report of a BLNK-deficient patient presenting with impaired memory B-cell and memory T-cell development. Furthermore, this study is the first reporting a pathogenic synonymous splice variant in BLNK.
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http://dx.doi.org/10.1016/j.clim.2020.108387DOI Listing
May 2020

Clinical and Molecular Characterization of Three Novel ARHGEF9 Mutations in Patients with Developmental Delay and Epilepsy.

J Mol Neurosci 2020 Jun 15;70(6):908-915. Epub 2020 Jan 15.

Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, 1678 Dongfang Road, Shanghai, 200127, People's Republic of China.

Mutations in the rho guanine nucleotide exchange factor 9 gene (ARHGEF9) are present in patients with heterogeneous phenotypes including psychomotor developmental delay and variable degrees of epilepsy. Malfunction of collybistin (CB) encoded by ARHGEF9 leading to impaired clustering of gephyrin-dependent glycine receptors and γ-aminobutyric acid type A (GABAα) receptors is a crucial pathogenic mechanism. Here, we report on three patients with epilepsy and mental retardation. We studied three male patients with epilepsy and mild to moderate mental retardation. We conducted targeted panel sequencing of genes known to cause inherited disorders. In vitro studies and transcriptional experiments were performed to evaluate the functional and splicing effects of these variants on CB. Two novel missense variants (p.I294T and p.R357I) and one novel splicing variant (c.381+3A>G) in ARHGEF9 were identified in the three patients, respectively. In vitro studies confirmed that the two missense variants disrupted CB-mediated accumulation of gephyrin in submembrane microclusters. Transcriptional experiments of the splicing variant revealed the presence of aberrant transcripts leading to truncated protein product. Significance: Our cases and functional studies enrich our understanding of the phenotypic and genotypic spectrum of ARHGEF9.
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http://dx.doi.org/10.1007/s12031-019-01465-yDOI Listing
June 2020

Biallelic ERBB3 loss-of-function variants are associated with a novel multisystem syndrome without congenital contracture.

Orphanet J Rare Dis 2019 11 21;14(1):265. Epub 2019 Nov 21.

Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, 1678 Dongfang Road, Shanghai, 200127, People's Republic of China.

Background: Gain-of-function pathogenic variants of the Erb-B2 receptor tyrosine kinase 3 (ERBB3) gene contribute to the occurrence and development of a variety of human carcinomas through activation of phosphatidylinositol 3-kinase (PI3K)/AKT and extracellular signal-regulated kinase (ERK) signaling. ERBB3 gene homozygous germline variants, whose loss of function may cause autosomal recessive congenital contractural syndrome, were recently identified. This study aims to identify the disease-causing gene in a Chinese pedigree with variable phenotypes involving multiple systems, including developmental delay, postnatal growth retardation, transient lower limb asymmetry, facial malformations, atrioventricular canal malformation, bilateral nystagmus and amblyopia, feeding difficulties, immunodeficiency, anemia, and liver damage, but without congenital contracture.

Methods: Trio-whole exome sequencing (WES) was performed to identify the disease-causing gene in a 24-month-old Chinese female patient. The pathogenicity of the identified variants was evaluated using in silico tools and in vitro functional studies.

Results: Trio-WES revealed compound heterozygous variants of c.1253 T > C (p.I418T) and c.3182dupA (p.N1061Kfs*16) in the ERBB3 gene. Functional studies showed that p.I418T resulted in normal expression of ERBB3, which was capable of interacting with ERBB2. However, the variant impaired ERBB3 phosphorylation, consequently blocking ERBB2 phosphorylation and AKT and ERK activation. The truncated protein resulting from the c.3182dupA variant also lacked the capacity to activate downstream signaling pathways.

Conclusions: We report the first patient with a novel multisystem syndrome disorder without congenital contracture resulting from biallelic loss-of-function variants of ERBB3.
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http://dx.doi.org/10.1186/s13023-019-1241-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868814PMC
November 2019

Clinical Presentation and Novel Pathogenic Variants among 68 Chinese Neurofibromatosis 1 Children.

Genes (Basel) 2019 10 26;10(11). Epub 2019 Oct 26.

Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center-Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.

Background: Neurofibromatosis 1 (NF1) is one of the most common dominantly inherited genetic disorders worldwide, with an age-dependent phenotypic expression. Exploring the mutational spectrum and clinical presentation of NF1 patients at different ages from a diverse population will aid the understanding of genotype-phenotype correlations.

Methods: In this study, 95 Chinese children with clinical suspicion of NF1 mainly due to the presence of multiple café-au-lait macules (CALMs) were subjected to medical exome-sequencing analysis and Sanger confirmation of pathogenic variants. Clinical presentations were evaluated regarding dermatological, ocular, neurological, and behavioral features.

Results: Pathogenic or likely pathogenic variants were detected in 71.6% (68/95) of patients; 20 pathogenic variants were not previously reported, indicating that Chinese NF1 patients are still understudied. Parental Sanger sequencing confirmation revealed 77.9% of de novo variants, a percentage that was much higher than expected. The presence of a higher number of NF1-related features at young ages was correlated with positive diagnostic findings. In addition to CALMs, neurological and behavioral features had a high expression among Chinese NF1 children. We attempted to correlate short stature with the locations of the pathogenic variants across the gene. It is interesting to notice that variants detected in the C-terminal region of the gene were less likely to be associated with short stature among the NF1 patients, whereas variants at the N-terminal were highly penetrant for the short stature phenotype.

Conclusion: Novel pathogenic variants are yet to be uncovered in under-studied NF1 patient populations; their identification will help to reveal novel genotype-phenotype correlations.
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http://dx.doi.org/10.3390/genes10110847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896037PMC
October 2019

De novo truncating variant in NSD2gene leading to atypical Wolf-Hirschhorn syndrome phenotype.

BMC Med Genet 2019 08 5;20(1):134. Epub 2019 Aug 5.

Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, 1678 Dongfang Road, Shanghai, 200127, People's Republic of China.

Background: Wolf-Hirschhorn syndrome (WHS) is a contiguous gene syndrome caused by partial 4p deletion highly variable in size in individual patients. The core WHS phenotype is defined by the association of growth delay, typical facial characteristics, intellectual disability and seizures. The WHS critical region (WHSCR) has been narrowed down and NSD2 falls within this 200 kb region. Only four patients with NSD2 variants have been documented with phenotypic features in detail.

Case Presentation: Herein, we report the case of a 12-year-old boy with developmental delay. He had dysmorphic facial features including wide-spaced eyes, prominent nasal bridge continuing to forehead, abnormal teething and micrognathia. He also had mild clinodactyly of both hands. Using whole-exome sequencing, we identified a pathogenic mutation in NSD2 [c.4029_4030insAA, p.Glu1344Lysfs*49] isolated from peripheral blood DNA. Sanger confirmation of this variant revealed it as a de novo truncating variant in the family.

Conclusion: Here, we reported a boy with de novo truncating variant in NSD2 with atypical clinical features comparing with 4p16.3 deletion related WHS. Our finding further supported the pathogenesis of truncating variants in NSD2 and delineated the possible symptom spectrum caused by these variants.
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http://dx.doi.org/10.1186/s12881-019-0863-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683463PMC
August 2019

[Identification of a novel SYNGAP1 mutation in a child with intellectual disability].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2019 Jul;36(7):716-719

Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200126, China.

Objective: To report on a child with mental retardation caused by SYNGAP1 gene mutation.

Methods: Peripheral blood samples were collected from the proband and her parents. High throughput sequencing (HTS) was employed for screening for potential mutation in the patient. Suspected mutation was validated by Sanger sequencing of the child and her parents.

Results: By HTS, a previously unknown mutation [c.1656C>A (p.C552*)] was found in exon 10 of the SYNGAP1 gene in the proband. Sanger sequencing confirmed the heterozygous nature of the mutation and that neither of her parents carried the same mutation.

Conclusion: The dysmorphism and developmental delay of the child were probably due to the pathogenic mutation of the SYNGAP1 gene. HTS can facilitate elucidation of the genetic etiology with efficiency, which has great significance in the diagnosis, treatment and prognosis of the child.
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http://dx.doi.org/10.3760/cma.j.issn.1003-9406.2019.07.015DOI Listing
July 2019

[Analysis of SATB2 gene mutation in a child with Glass syndrome].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2019 Jul;36(7):712-715

Department of Clinical Laboratory, Jinhua Central Hospital, Jinhua, Zhejiang 321000, China.

Objective: To analyze the clinical characteristics and genetic basis of a child affected with Glass syndrome.

Methods: Clinical manifestations and auxiliary examination results of the child were analyzed. Potential mutation was detected with next generation sequencing and validated by Sanger sequencing.

Results: The child has featured growth and mental retardation, delayed speech, cleft palate, crowding of teeth, and downslanting palpebral fissures. DNA sequencing revealed a de novo heterozygous missense mutation c.1166G>A (p.R389H) in exon 8 of the SATB2 gene in the child.

Conclusion: The heterozygous mutation c.1166G>A (p.R389H) of the SATB2 gene probably account for the Glass syndrome in the patient.
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http://dx.doi.org/10.3760/cma.j.issn.1003-9406.2019.07.014DOI Listing
July 2019

TRMA syndrome with a severe phenotype, cerebral infarction, and novel compound heterozygous SLC19A2 mutation: a case report.

BMC Pediatr 2019 07 11;19(1):233. Epub 2019 Jul 11.

Department of Endocrinology and Metabolism, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, 1678 Dongfang Road, Pudong New Area, Shanghai, 200127, China.

Background: Thiamine-responsive megaloblastic anemia (TRMA) is a rare autosomal recessive inherited disease characterized by the clinical triad of megaloblastic anemia, sensorineural deafness, and diabetes mellitus. To date, only 100 cases of TRMA have been reported in the world.

Case Presentation: Here, we describe a six-year-old boy with diabetes mellitus, anemia, and deafness. Additionally, he presented with thrombocytopenia, leukopenia, horizontal nystagmus, hepatomegaly, short stature, ventricular premature beat (VPB), and cerebral infarction. DNA sequencing revealed a novel compound heterozygous mutation in the SLC19A2 gene: (1) a duplication c.405dupA, p.Ala136Serfs*3 (heterozygous) and (2) a nucleotide deletion c.903delG p.Trp301Cysfs*13 (heterozygous). The patient was diagnosed with a typical TRMA.

Conclusion: Novel mutations in the SLC19A2 gene have been identified, expanding the mutation spectrum of the SLC19A2 gene. For the first time, VPB and cerebral infarction have been identified in patients with TRMA syndrome, providing a new understanding of the phenotype.
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http://dx.doi.org/10.1186/s12887-019-1608-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625038PMC
July 2019

New insights from unbiased panel and whole-exome sequencing in a large Chinese cohort with disorders of sex development.

Eur J Endocrinol 2019 Sep;181(3):311-323

Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Context: Diagnosis of non-chromosomal type disorders of sex development (DSD) has long been challenging. There is still no research on overview of a large Chinese DSD cohort.

Objective: To determine the etiologic diagnosis through unbiased large-scale panel sequencing and whole-exome sequencing (WES) within a large Chinese DSD cohort.

Design: Patients were recruited according to the inclusion criteria of DSD. The applied panel contains 2742 known disease-causing genes, including all known diagnostic genes for DSD.

Methods: Targeted panel sequencing (TPS) was performed, and identified candidate variants were verified. Variant pathogenicities were evaluated according to established guidelines. WES was performed for randomly selected negative samples.

Results: This study included 125 patients. Seventy-five variants were identified by TPS and 31 variants were reported for the first time. Pathogenic and likely pathogenic variants accounted for 38.7 and 30.7%, respectively. On the basis of clinical certainty, etiologic diagnostic rates of 46.9 and 10.3% were obtained for 46,XY and 46,XX DSD patients, respectively. We reported novel candidate genes (BMPR1B, GNAS, GHR) and regions of copy number variants outside the expected DSD genotype-phenotype correlation and determined a founder mutation (SRD5A2 p.R227Q) in patients with 5α-reductase deficiency. Further WES in randomly selected negative samples identified only one among 14 negative samples as a variant of uncertain significance, indicating that WES did not improve the diagnostic rate.

Conclusions: This is the first report of the applying unbiased TPS in a large Chinese cohort of patients with 46,XY and 46,XX DSD. Our findings expand the gene, mutation and phenotype spectra of the rare types of DSD in the Chinese population and provide new insight into the current understanding of the etiologies of DSD.
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http://dx.doi.org/10.1530/EJE-19-0111DOI Listing
September 2019

Molecular and phenotypic spectrum of Noonan syndrome in Chinese patients.

Clin Genet 2019 10 10;96(4):290-299. Epub 2019 Jul 10.

Department of Endocrinology and Metabolism, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.

Noonan syndrome (NS) is a common autosomal dominant/recessive disorder. No large-scale study has been conducted on NS in China, which is the most populous country in the world. Next-generation sequencing (NGS) was used to identify pathogenic variants in patients that exhibited NS-related phenotypes. We assessed the facial features and clinical manifestations of patients with pathogenic or likely pathogenic variants in the RAS-MAPK signaling pathway. Gene-related Chinese NS facial features were described using artificial intelligence (AI).NGS identified pathogenic variants in 103 Chinese patients in eight NS-related genes: PTPN11 (48.5%), SOS1 (12.6%), SHOC2 (11.7%), KRAS (9.71%), RAF1 (7.77%), RIT1 (6.8%), CBL (0.97%), NRAS (0.97%), and LZTR1 (0.97%). Gene-related facial representations showed that each gene was associated with different facial details. Eight novel pathogenic variants were detected and clinical features because of specific genetic variants were reported, including hearing loss, cancer risk due to a PTPN11 pathogenic variant, and ubiquitous abnormal intracranial structure due to SHOC2 pathogenic variants. NGS facilitates the diagnosis of NS, especially for patients with mild/moderate and atypical symptoms. Our study describes the genotypic and phenotypic spectra of NS in China, providing new insights into distinctive clinical features due to specific pathogenic variants.
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http://dx.doi.org/10.1111/cge.13588DOI Listing
October 2019

Evaluation of copy number variant detection from panel-based next-generation sequencing data.

Mol Genet Genomic Med 2019 01 22;7(1):e00513. Epub 2018 Nov 22.

Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.

Background: Targeted gene capture and next-generation sequencing (NGS) has been widely utilized as a robust and cost-effective approach for detecting small variants among a group of disease genes. Copy number variations (CNV) can also be inferred from the read-depth information but the accuracy of CNVs called from panel-based NGS data has not been well evaluated.

Methods: Sequencing data were acquired from patients underwent routine clinical targeted panel sequencing testing. Pathogenic CNVs detected from targeted panel sequencing data were evaluated using CNVs generated by two clinical accepted platforms, namely chromosome microarray analysis (CMA) and multiple ligation-dependent probe amplification (MLPA) as benchmarks. CNVkit was used in our study to call CNVs from sequencing data using read-depth information. CMA and MLPA tests were used to confirm and further assess the size and breakpoints of CNVs.

Results: The size of CNVs detected using panel-based NGS data are over 300 kb. The sizes of CNVs detected are slightly larger (102.3% on average) using the NGS platform than using the CMA platform, and the size accuracy improved as the size of variants increases. The breakpoints of CNVs detected using NGS data are quite close (within 2.3% of margin) to the breakpoints detected by CMA. CNVs on sex chromosomes, however, are less concordant between NGS and CMA platforms.

Conclusion: Copy number variations covering adequate exons on autosomes can be accurately detected using targeted panel sequencing data as using CMA. CNVs detected from sex chromosomes need further evaluation and validation. Except for exon-level deletion/duplication and CNV on sex chromosome, our data support the use of panel-based NGS data for routine clinical detection of pathogenic CNVs.
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http://dx.doi.org/10.1002/mgg3.513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382442PMC
January 2019

Increased transactivation and impaired repression of β-catenin-mediated transcription associated with a novel SOX3 missense mutation in an X-linked hypopituitarism pedigree with modest growth failure.

Mol Cell Endocrinol 2018 12 17;478:133-140. Epub 2018 Aug 17.

Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China. Electronic address:

SOX3, a transcription factor of the SRY-related high mobility group box family, has been implicated in the etiology of X-linked hypopituitarism. Here, we report a Chinese pedigree of X-linked hypopituitarism with variable phenotypes. Despite the complete growth hormone deficiency, the growth failure of the patients was relatively modest. A rare point variant of SOX3 (c.424C > A; p. P142T) was identified in the pedigree via target panel sequencing. An in vitro study showed that both the expression and nuclear targeting of SOX3 remained unaffected by the variant. However, increased transcriptional activation and impaired repression of β-catenin-mediated transcription were noticed as a result of the SOX3 variant. This is the first study to report that the rare SOX3 missense variant associated with hypopituitarism possibly due to increased activation of SOX3 target genes and disregulation of β-catenin target genes. In addition, we have expanded the phenotypic spectrum associated with SOX3 mutations.
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http://dx.doi.org/10.1016/j.mce.2018.08.006DOI Listing
December 2018

Concurrent somatic KRAS mutation and germline 10q22.3-q23.2 deletion in a patient with juvenile myelomonocytic leukemia, developmental delay, and multiple malformations: a case report.

BMC Med Genomics 2018 Jul 16;11(1):60. Epub 2018 Jul 16.

Department of Pediatric Surgery, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, 200127, People's Republic of China.

Background: The proto-oncogene KRAS performs an essential function in normal tissue signaling, and the mutation of KRAS gene is a key step in the development of many cancers. Somatic KRAS mutations are often detected in patients with solid and non-solid tumors, whereas germline KRAS mutations are implicated in patients with the Noonan syndrome, cardio-facio-cutaneous (CFC) syndrome and Costello syndrome. The deletion of chromosome 10q22.3-q23.2 is a rare cytogenetic abnormality, which often leads to distinct facial appearance and delays in speech and global development.

Case Presentation: Herein, we report the case of a 4-year-old boy diagnosed with juvenile myelomonocytic leukemia. The boy also had syndromic features, such as speech and motor developmental delay, multiple congenital malformations, including distinct facial features, club feet, and cryptorchidism. Using whole-exome sequencing, we identified a pathogenic mutation in KRAS [c.34G > A, p.Gly12Ser] isolated from peripheral blood DNA. Sanger sequencing confirmed the wild-type sequence in the parents and patient's salivary cell DNA indicating its somatic state. A 7311-kb deletion in 10q22.3-q23.2 was also revealed by chromosomal microarray analysis, which was later proved as a germline de novo variant.

Conclusion: Juvenile myelomonocytic leukemia in the patient was attributed to a somatic KRAS mutation, whereas the syndromic features of the patient were considered a consequence of germline chromosome 10q22.3-q23.2 deletion. Genetic testing for patients with complicated phenotypes can be valuable in detecting multiple pathogenic variants.
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http://dx.doi.org/10.1186/s12920-018-0377-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048798PMC
July 2018
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