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1.
Eur J Endocrinol ; 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31277073

RESUMO

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 2,742 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.

2.
Orphanet J Rare Dis ; 14(1): 144, 2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31200758

RESUMO

BACKGROUND: Floating-Harbor syndrome (FHS) is a rare syndromic short stature disorder caused by truncating variants in SRCAP. Few Chinese FHS patients had been reported so far and limited knowledge regarding the benefit of growth hormone treatment existed. METHODS: We ascertained 12 short stature patients with molecularly confirmed diagnosis of FHS by whole exome sequencing. We performed a comprehensive clinical evaluation for all patients and assessed the responsiveness of growth hormone treatment in a subset of the patients. RESULTS: Five distinct pathogenic/likely pathogenic variants were identified in 12 independent FHS patients including two previously reported variants (c.7303C > T/p.Arg2435Ter and c.7330C > T/p.Arg2444Ter) and three novel variants (c.7189G > T/p.Glu2397Ter, c.7245_7246delAT/p.Ser2416ArgfsTer26 and c.7466C > G/p.Ser2489Ter). The c.7303C > T/p.Arg2435Ter mutation appears more common in Chinese FHS patients. The clinical presentations of Chinese FHS patients are very similar to those of previously reported patients of different ethnicities. Yet we noticed micropenis and ear abnormalities in multiple patients, suggesting that these may be novel phenotypes of Floating-Harbor syndrome. Eight patients (one with GH deficiency, one with undetermined GH level, six without GH deficiency) underwent growth hormone treatment, 3 patients had good responses, one with modest and two with poor responses. CONCLUSION: We described novel genotypes and phenotypes in a Chinese FHS patient cohort. We showed that about half of FHS patients exhibited modest to good response to GH treatment regardless of their respective GH deficiency status. We didn't find any correlation between different mutations and response to GH treatment.

3.
Am J Med Genet C Semin Med Genet ; 181(2): 170-176, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30860676

RESUMO

The rapid development of genetic and genomic technologies has greatly boosted medical genetic researches and clinical services worldwide. Since last century, genetic counseling in the United States has helped individuals and families understand, accept, and cope with their genetic issues. This fledging profession, which is in essence a branch of social work, emerged in China relatively late but has rapidly grown over the last few years. We believe that genetic counseling will continue to play a pivotal role in building communication channels between medical doctors and their patients, the government and the general public, and social organizations and their customers in China. The growth of genetic counseling aims to enable patients and family members to make informed decision which in turn will lead to the reduction of the birth prevalence of severe congenital anomalies and genetic disorders.

4.
Medicine (Baltimore) ; 98(8): e14519, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30813154

RESUMO

To understand the risks associated with aplastic anemia (AA) in 4 cities of Zhejiang Province, China, with special focus on the joint contributions of multiple risks.Based on an Electronic Data Capture (EDC), a case control study was carried out. Data regarding socio-demographic, diseases history, living habits, and exposures to toxic substances, etc., were collected through survey questionnaires. t Test, chi-square test, or non-parametric rank sum test, and univariate and multivariate Logistic regression analysis were conducted to analyze data.The univariate logistic regression analysis results indicated that among all study participants (n = 1802), AA was associated with over 30 risks, in terms of their individual behaviors, daily and environmental exposures, diseases history, and family history. Multivariate logistic regression analysis further confirmed that the independent risks related to AA included presence of chemical factory within 3 km of living residence (odds ratio [OR] = 8.73, 95% CI: 1.42-53.74, P = .019), living in a newly decorated house/apartment (OR = 25.37, 95% CI: 4.44-144.81, P < .001), vegetarian diet (OR = 131.60, 95% CI: 3.45-5020.16, P = .009), preference of sugar (OR = 89.38, 95% CI: 7.22-1106.44, P < .001), preference of oily food (OR = 55.68, 95% CI: 5.12-605.26, P = .001), drinking lake water or pond water (OR = 58.05, 95% CI: 3.21-1049.81, P < .001), habit of staying up late (OR = 11.87, 95% CI: 3.43-41.02, P < .001), infection history (OR = 10.08, 95% CI: 2.75-36.93, P < .001). Result of receiver operating characteristic curve (ROC) analysis on the joint contribution of multiple risks indicated that AA was 13.835 times likely to occur when exposed to ≥1 risks than those exposed to 0 risks (95% CI: 9.995-19.149).Our study results demonstrated a comprehensive epidemiological pattern, in which the joint contributions of individual inherited health status, environment exposure, and individual behaviors lead to the occurrence of AA.


Assuntos
Anemia Aplástica/etiologia , Medição de Risco/métodos , Adolescente , Adulto , Idoso , Anemia Aplástica/epidemiologia , Estudos de Casos e Controles , Criança , Pré-Escolar , China/epidemiologia , Exposição Ambiental/efeitos adversos , Feminino , Comportamentos Relacionados com a Saúde/etnologia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Inquéritos e Questionários , Adulto Jovem
5.
Am J Med Genet C Semin Med Genet ; 181(2): 218-225, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30893510

RESUMO

CCCTC-binding factor (CTCF) is an important regulator for global genomic organization and gene expression. CTCF gene had been implicated in a novel disorder characterized by intellectual disability, feeding difficulty, developmental delay and microcephaly. So far, four patients have been reported with de novo CTCF mutations. We reported three additional Chinese patients with de novo variants in CTCF. The new evidence helped to establish the clinical validity between CTCF and the emerging disorder. We described the consistent phenotypes shared by all patients and revealed additional clinical features such as delayed or abnormal teeth development and a unique pattern of the eyebrow that may help to define a potential recognizable neurodevelopmental disorder. We also reported the first CTCF patient treated with recombinant human growth hormone. Follow-up and more case studies will further our understanding to the clinical presentations of this novel disorder and the prognosis of patients with this disorder.

8.
Mol Genet Genomic Med ; 7(4): e00596, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30729726

RESUMO

BACKGROUND: Heterozygous mutations in the AT-hook DNA-binding motif containing one (AHDC1, OMIM * 615790) gene cause an autosomal dominant multisystem developmental disorder known as Xia-Gibbs syndrome (OMIM #615829). Xia-Gibbs syndrome typically presented with global developmental delay, hypotonia, obstructive sleep apnea, seizures, delayed myelination, micrognathia, and other mild dysmorphic features. METHODS: Description of the clinical materials of two Chinese boys who were diagnosed with Xia-Gibbs syndrome based on clinical presentations and next generation sequencing. Review of clinical features and AHDC1 mutations in previously reported Xia-Gibbs syndrome patients together with our two new patients. RESULTS: The Xia-Gibbs syndrome patients exhibited short stature, hypotonia, global developmental delay, speech delay, simian crease, and mild dysmorphic features. Next generation sequencing revealed de novo heterozygous variants in AHDC1 gene. In addition, laboratory test revealed partial growth hormone deficiency. Both patients underwent growth hormone replacement therapy for 24 and 9 months, respectively, and exhibited good response to the treatment. CONCLUSION: This is the first report of Xia-Gibbs syndrome patients to be treated with growth hormone. Review of previously reported Xia-Gibbs syndrome patient indicated that short stature is a frequent feature of this condition, but its underlying cause needs to be further investigated.


Assuntos
Proteínas de Ligação a DNA/genética , Nanismo Hipofisário/genética , Criança , Pré-Escolar , Nanismo Hipofisário/tratamento farmacológico , Nanismo Hipofisário/patologia , Hormônio do Crescimento/uso terapêutico , Heterozigoto , Humanos , Masculino , Mutação
9.
Fetal Pediatr Pathol ; 38(1): 44-56, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30633617

RESUMO

BACKGROUND: Biallelic pathogenic variants in CYP24A1 can cause idiopathic infantile hypercalcemia (HCINF). METHODS: We report 2 additional molecular abnormalities in 2 Chinese children with CHINF1. RESULTS: Biallelic variants in CYP24A1 were found in two patients. Patient One was compound heterozygous for c.449 + 1G > T and c.1426_1427delCT. Patient Two was compound heterozygous for c.1310C > A and c.1426_1427delCT. The c.1310C > A and c.449 + 1G > T were two different novel CYP24A1 variants. Multiple computational tools predicted that both impact protein function. A total of 36 variants have been previously reported in patients with HCINF1, of which 27 were classified as pathogenic or likely pathogenic and nine as uncertain clinical significance. CONCLUSION: Genetic tests are helpful in order to counsel the susceptible individuals to avoid vitamin D and take preventive measures in order to avoid complications.


Assuntos
Hipercalcemia/genética , Doenças do Recém-Nascido/genética , Erros Inatos do Metabolismo/genética , Vitamina D3 24-Hidroxilase/genética , Grupo com Ancestrais do Continente Asiático/genética , Feminino , Variação Genética , Humanos , Lactente , Masculino , Linhagem
10.
Mol Genet Genomic Med ; 7(1): e00513, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30565893

RESUMO

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.


Assuntos
Testes Genéticos/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Análise de Sequência de DNA/métodos , Variações do Número de Cópias de DNA , Testes Genéticos/normas , Sequenciamento de Nucleotídeos em Larga Escala/normas , Humanos , Distrofia Muscular de Duchenne/genética , Sensibilidade e Especificidade , Análise de Sequência de DNA/normas
11.
Fetal Pediatr Pathol ; 37(6): 404-410, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30592236

RESUMO

BACKGROUND: Short stature with optic atrophy and Pelger-Huet anomaly (SOPH; MIM 614800) syndrome is a genetic disease caused by mutation in the neuroblastoma amplified sequence (NBAS) gene. CASE REPORT: We present a 11-year-old Chinese boy with SOPH syndrome, growth hormone deficiency with a normal bone age. Gene sequencing in the patient revealed a novel compound heterozygous mutation of c.5752A > C (Thr1918Pro) and c.500_501delTT (Phe167Cysfs*7) in the NBAS gene. CONCLUSIONS: To our best knowledge, these novel mutations in the NBAS gene have not been reported. Normal bone age with growth hormone deficiency in this patient is different from the patients with SOPH syndrome that have been previously reported. These findings enrich the mutant spectrum of the NBAS gene and add our understanding of SOPH syndrome.


Assuntos
Hormônio do Crescimento Humano/deficiência , Proteínas de Neoplasias/genética , Anomalia de Pelger-Huët/genética , Estatura/genética , Desenvolvimento Ósseo/genética , Criança , Humanos , Masculino
12.
J Med Chem ; 2018 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-30407821

RESUMO

Spinal muscular atrophy (SMA), a rare neuromuscular disorder, is the leading genetic cause of death in infants and toddlers. SMA is caused by the deletion or a loss of function mutation of the survival motor neuron 1 (SMN1) gene. In humans, a second closely related gene SMN2 exists, however it codes for a less stable SMN protein. In recent years, significant progress has been made toward disease modifying treatments for SMA by modulating SMN2 pre-mRNA splicing. Herein, we describe the discovery of LMI070 / branaplam, a small molecule that stabilizes the interaction between the spliceosome and SMN2 pre-mRNA. Branaplam (1) originated from a high-throughput phenotypic screening hit, pyridazine 2, and evolved via multi-parameter lead optimization. In a severe mouse SMA model, branaplam treatment increased full-length SMN RNA and protein levels, and extended survival. Currently, branaplam is in clinical studies for SMA.

13.
Artigo em Inglês | MEDLINE | ID: mdl-30444213

RESUMO

OBJECTIVES: The LHCGR gene encodes a G-protein coupled receptor that plays a pivotal role in sexual differentiation in males, ovarian development in females, and in fertility via its interaction with luteinizing hormone (LH) and chorionic gonadotropin (CG). Inactive variants of the LHCGR gene cause Leydig cell hypoplasia (LCH), which is a rare disease and one of the causes of disorder of sexual differentiation (DSD) in males. The aim of this work is to study the clinical and molecular characteristics of a 2-year-9-month old patient with type 1 LCH. METHODS: Whole-exome sequencing was performed for the patient family, and variants in the LHCGR gene were validated by Sanger sequencing. Pathogenicity of the missense variant was evaluated by multiple in silico tools. RESULTS: The Chinese patient, who exhibits DSD, has female external genitalia (normal labia majora and minora, external opening of urethra under the clitoris and blind-ended vagina) and bilateral testis tissues in the inguinal region. Genetic sequencing revealed compound heterozygous variants in the LHCGR gene in the patient, including a novel missense variant in exon 4 (c.349G>A, p.Gly117Arg) and a novel nonsense variant in exon 10 (c.878C>A, p.Ser293*). The missense variant is in the first leucine-rich repeat (LRR) domain of the LHCGR protein, which is predicted to affect ligand recognition and binding affinity and thus protein function. CONCLUSIONS: The patient is molecularly and clinically diagnosed with type 1 LCH, which is caused by novel, compound heterozygous variants of the LHCGR gene. This report expanded the genotypic spectrum of LHCGR variants.

14.
BMC Med Inform Decis Mak ; 18(1): 91, 2018 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-30400925

RESUMO

BACKGROUND: Trio studies, which involve the testing of samples from a proband and both parents, are often used by clinical laboratories to help with the classification of genetic variants, including copy number variants. In order for the results of the trio study to be valid, the mother and father must be the true biological parents of the proband. As such, non-paternity and sample mix-ups are potential sources of error. To address these potential issues, we developed a computer script to accurately assess maternity and paternity using single nucleotide polymorphism (SNP) data generated by Agilent chromosomal microarrays, a platform-of-choice for clinical copy number testing. RESULTS: We assessed the performance of the script on 10 putative trios tested at our laboratory, and found that the numbers and proportions of discordant SNPs were useful for determining parental relationships. The results of the assessment also confirmed maternity and paternity in the 10 trios tested, and by doing so essentially excluded pre-analytical sample switching in these 30 samples. CONCLUSIONS: Computational analysis of SNP data can be implemented as a quality control measure for trio testing performed on Agilent microarrays.

15.
Clin Chim Acta ; 487: 264-269, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30292630

RESUMO

BACKGROUND: Primary hypertrophic osteoarthropathy (PHO) is a genetically and clinically heterogeneous systematic disorder caused by mutations in genes HPGD and SLCO2A1. The purpose of the present study is to provide useful information for the early and precise diagnosis of PHO and identify causative mutations in Chinese PHO children. METHODS AND RESULTS: The clinical manifestations, radiographic features of seven Chinese pediatric patients were systematically analyzed. Targeted exome sequencing identified a previously reported c.310_311delCT mutation and a novel common splicing site mutation c.324 + 5G > A in the HPGD gene. Relative quantitative real time PCR validated a novel deletion of the exon 4 in the same gene. Neither mutations nor structural variations in the gene SLCO2A1 were detected. CONCLUSIONS: In the present study, homozygous or compound heterozygous HPGD mutations were identified in seven Chinese pediatric patients, suggesting an autosomal recessive inheritance. The c.310_311delCT mutation and the splicing site mutation c.324 + 5G > A were likely to be mutational hotspots in Chinese PHO patients. For the first time, a structural variation of the HPGD gene was reported. Homozygous, compound heterozygous mutations or structural variation identified in the HPGD gene proposed that targeted exome sequencing may be a preferable method for pediatric PHO diagnosis and mutation analysis.

16.
Orphanet J Rare Dis ; 13(1): 178, 2018 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-30305169

RESUMO

BACKGROUND: Wiedemann-Steiner syndrome (WDSTS) is a rare genetic disorder characterized by facial gestalt, neurodevelopmental delay, skeletal anomalies and growth retardation, which is caused by variation of KMT2A gene. To date, only 2 Chinese WDSTS patients have been reported. Here, we report the phenotypes and KMT2A gene variations in 14 unrelated Chinese WDSTS patients and investigate the phenotypic differences between the Chinese and French cohorts. METHODS: Next generation sequencing was performed for each patient, and the variants in the KMT2A gene were validated by Sanger sequencing. The phenotypes of 16 Chinese WDSTS patients were summarized and compared to 33 French patients. RESULTS: Genetic sequencing identified 13 deleterious de novo KMT2A variants in 14 patients, including 10 truncating, 2 missenses and 1 splicing variants. Of the 13 variants, 11 are novel and two have been reported previously. One of the patients is mosaic in the KMT2A gene. The variation spectra and phenotypic profiles of the Chinese WDSTS patients showed no difference with patients of other ethnicities; however, differ in the frequencies of several clinical features. We demonstrated that variations in the KMT2A gene can lead to both advanced and delayed bone age. We identified 6 novel phenotypes, which include microcephaly, deep palmar crease, external ear deformity, carpal epiphyseal growth retardation, dyslipidemia, and glossoptosis. In addition, patients harbored missense variants in the CXXC zinc finger domain of KMT2A showed more severe neurophenotypes. CONCLUSION: Our study consists of the largest cohort of Chinese WDSTS patients that continues to expand the WDSTS phenotypic and variation spectrum. Our results support the notion that the CXXC zinc finger domain of KMT2A gene is a hotspot for missense variants associated with more severe neurophenotypes.

17.
J Cell Biochem ; 2018 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-30230583

RESUMO

OBJECTIVE: Vascular endothelial growth factor (VEGF)-Notch signaling pathway plays an important role in aplastic anemia (AA). This study aimed to evaluate the regulatory roles of VEGF-Notch signaling pathway on mesenchymal stem cells (MSCs) isolated from AA patients with kidney deficiency and blood stasis (KB) (AA MSCs). METHODS: Expression of VEGF-Notch signaling related factors, including VEGF, VEGFR, Notch-1, Jagged1, Delta-like1, and hes1 was detected in bone marrow (BM) tissues and AA MSCs by Western blot analysis. VEGF (100 ng/mL) and γ-secretase inhibitor (DAPT) (10 µM) was used to active and inhibit VEGF-Notch signaling in AA MSCs, respectively. After treatment, the proliferation, apoptosis, and adipogenic differentiation of AA MSCs was detected by Cell Counting Kit-8, flow cytometry, and Oil red O staining, respectively. Lentivirus short hairpin RNA (shRNA) were constructed to downregulate Notch-1 and VEGF in normal bone marrow mesenchymal stem cells (BMSCs), and the effects of VEGF/Notch-1 shRNA transfected BMSCs on the proliferation, migration, and angiogenesis of human umbilical vein endothelial cells (HUVECs) were evaluated. RESULTS: Significantly lower expression of VEGF, VEGFR, Notch-1, Jagged1, Delta-like1, and hes1 was revealed in AA BM tissues and AA MSCs when compared with the normal control (P < 0.05). The intervention of DAPT significantly inhibited the proliferation, and promoted the apoptosis and adipogenic differentiation of AA MSCs, while VEGF intervention exhibited opposite results (P < 0.05). Meanwhile, the proliferation, migration, and angiogenesis of HUVECs were significantly promoted by normal BMSCs, while inhibited by VEGF/Notch-1 shRNA transfected BMSCs (P < 0.05). CONCLUSION: The activation of VEGF-Notch signaling pathway may be a potential therapeutic target for AA with KB.

18.
Mol Cell Endocrinol ; 478: 133-140, 2018 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-30125608

RESUMO

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 ß-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 ß-catenin target genes. In addition, we have expanded the phenotypic spectrum associated with SOX3 mutations.

19.
J Hum Genet ; 63(11): 1119-1128, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30115950

RESUMO

Intracranial vertebral-basilar artery dissection (IVAD) is an arterial disorder leading to life-threatening consequences. Genetic factors are known to be causative to certain syndromic forms of IVAD. However, systematic study of the molecular basis of sporadic and isolated IVAD is lacking. To identify genetic variants contributing to the etiology of IVAD, we enrolled a cohort of 44 unrelated cases with a clinical diagnosis of isolated IVAD and performed whole-exome sequencing (WES) for all the participants; a trio exome sequencing approach was used when samples from both parents were available. Four previously reported disease-causing heterozygous variants (three in COL3A1 and one in FBN1) and seven novel heterozygous variants in IVAD-related genes were identified. In addition, six variants in novel IVAD genes including two de novo heterozygous nonsynonymous variants (each in VPS52 and CDK18), two stop-gain variants (each in MYH9 and LYL1), and two heterozygous biallelic variants in TNXB were considered to be possibly contributing to the phenotype, with unknown significance according to the existing knowledge. A significantly higher mutational rate of IVAD candidate genes was observed in patients versus our in-house controls (P = 0.002) (DISCO study, http://www.discostudy.org/ , n = 2248). Our study provided a mutational landscape for patients with isolated IVAD.

20.
Am J Med Genet B Neuropsychiatr Genet ; 177(6): 589-595, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30076746

RESUMO

Members of the neurexin gene family, neurexin 1 (NRXN1), neurexin 2 (NRXN2), and neurexin 3 (NRXN3) encode important components of synaptic function implicated in autism and other neurodevelopmental/neuropsychiatric disorders. Loss of function variants have been reported predominantly in NRXN1, with fewer such variants detected in NRXN2 and NRXN3. Evidence for segregating NRNX3 variants has particularly been lacking. Here, we report identification by chromosomal microarray analysis of a rare exonic deletion affecting the NRXN3 alpha isoform in a three-generation Chinese family. The proband, a 7-year-old boy, presented with motor and language delay and met the clinical diagnostic criteria for autism. He also presented with moderate intellectual disability, attention-deficit hyperactivity disorder and facial dysmorphic features. The mother and maternal grandfather, both deletion carriers, presented with variable degrees of language and communication difficulties, as well as neuropsychiatric problems such as schizophrenia and temper tantrums. A compilation of sporadic cases with deletions involving part or all of NRXN3 revealed that 9 of 23 individuals (39%) displayed features of autism. The evidence for cosegregation in our family further supports a role for NRXN3 in autism and neurodevelopmental/neuropsychiatric disorders but demonstrates intrafamily variable expressivity due to this NRXN3 deletion, with schizophrenia and facial dysmorphism being potential novel features of NRXN3 haploinsufficiency.

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