scholarly journals Novel MFSD8 Variants in a Chinese Family with Nonsyndromic Macular Dystrophy

2021 ◽  
Vol 2021 ◽  
pp. 1-5
Author(s):  
Qin Xiang ◽  
Yanna Cao ◽  
Hongbo Xu ◽  
Zhijian Yang ◽  
Liang Tang ◽  
...  
Keyword(s):  
Family Members ◽  
Major Facilitator Superfamily ◽  
Chinese Family ◽  
Macular Dystrophy ◽  
Compound Heterozygous ◽  
The Novel ◽  
Pathogenic Variants ◽  
Compound Heterozygous Variants ◽  
Major Facilitator ◽  
Mfsd8 Gene

Purpose. To identify the molecular etiology of a Chinese family with nonsyndromic macular dystrophy. Methods. Ophthalmic examinations were performed, and genomic DNA was extracted from available family members. Whole exome sequencing of two members (the proband and her unaffected mother) and Sanger sequencing in available family members were performed to screen potential pathogenic variants. Results. Novel compound heterozygous variants, c.1066C>T (p.Pro356Ser) and c.1102+2T>C, in the major facilitator superfamily domain containing 8 gene (MFSD8) were suspected to be involved in this family’s macular dystrophy phenotype. The novel c.1066C>T variant in the MFSD8 gene probably resulted in substitution of serine for proline at the 356th residue and was predicted to be “uncertain significance” through in silico analyses. The novel c.1102+2T>C variant in the MFSD8 gene was likely to affect the splicing form and predicted to be “pathogenic.” Conclusion. The novel compound heterozygous variants, c.1066C>T (p.Pro356Ser) and c.1102+2T>C, in the MFSD8 gene are likely responsible for the isolated macular dystrophy phenotype in this family. This study enlarged the MFSD8 gene mutant spectrum and might provide more accurate genetic counseling for this family.

scholarly journals Novel compound heterozygous EYS variants may be associated with arRP in a large Chinese pedigree

2020 ◽  
Vol 40 (6) ◽  
Author(s):  
Chunli Wei ◽  
Ting Xiao ◽  
Jingliang Cheng ◽  
Jiewen Fu ◽  
Qi Zhou ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Gene Mutations ◽  
Chinese Family ◽  
Compound Heterozygous ◽  
Missense Mutations ◽  
The Novel ◽  
Pathogenic Variants ◽  
Pathogenic Genes ◽  
Compound Heterozygous Variants ◽  
Normal Controls

Abstract As a genetically heterogeneous ocular dystrophy, gene mutations with autosomal recessive retinitis pigmentosa (arRP) in patients have not been well described. We aimed to detect the disease-causing genes and variants in a Chinese arRP family. In the present study, a large Chinese pedigree consisting of 31 members including a proband and another two patients was recruited; clinical examinations were conducted; next-generation sequencing using a gene panel was used for identifying pathogenic genes, and Sanger sequencing was performed for verification of mutations. Novel compound heterozygous variants c.G2504A (p.C835Y) and c.G6557A (p.G2186E) for the EYS gene were identified, which co-segregated with the clinical RP phenotypes. Sequencing of 100 ethnically matched normal controls didn’t found these mutations in EYS. Therefore, our study identified pathogenic variants in EYS that may cause arRP in this Chinese family. This is the first study to reveal the novel mutation in the EYS gene (c.G2504A, p.C835Y), extending its mutation spectrum. Thus, the EYS c.G2504A (p.C835Y) and c.G6557A (p.G2186E) variants may be the disease-causing missense mutations for RP in this large arRP family. These findings should be helpful for molecular diagnosis, genetic counseling and clinical management of arRP disease.

scholarly journals DNAH11 compound heterozygous variants cause heterotaxy and congenital heart disease

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0252786
Author(s):  
Hong Xia ◽  
Xiangjun Huang ◽  
Sheng Deng ◽  
Hongbo Xu ◽  
Yan Yang ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Exome Sequencing ◽  
Sanger Sequencing ◽  
Congenital Heart ◽  
Chinese Family ◽  
Compound Heterozygous ◽  
Internal Organs ◽  
Pathogenic Variants ◽  
Compound Heterozygous Variants

Heterotaxy (HTX), a condition characterized by internal organs not being arranged as expected relative to each other and to the left-right axis, is often accompanied with congenital heart disease (CHD). The purpose was to detect the pathogenic variants in a Chinese family with HTX and CHD. A non-consanguineous Han Chinese family with HTX and CHD, and 200 unrelated healthy subjects were enlisted. Exome sequencing and Sanger sequencing were applied to identify the genetic basis of the HTX family. Compound heterozygous variants, c.3426-1G>A and c.4306C>T (p.(Arg1436Trp)), in the dynein axonemal heavy chain 11 gene (DNAH11) were identified in the proband via exome sequencing and further confirmed by Sanger sequencing. Neither c.3426-1G>A nor c.4306C>T variant in the DNAH11 gene was detected in 200 healthy controls. The DNAH11 c.3426-1G>A variant was predicted as altering the acceptor splice site and most likely affecting splicing. The DNAH11 c.4306C>T variant was predicted to be damaging, which may reduce the phenotype severity. The compound heterozygous variants, c.3426-1G>A and c.4306C>T, in the DNAH11 gene might be the pathogenic alterations resulting in HTX and CHD in this family. These findings broaden the variant spectrum of the DNAH11 gene and increase knowledge used in genetic counseling for the HTX family.

scholarly journals Case Report: Novel Compound Heterozygous Variants in TRIOBP Associated With Congenital Deafness in a Chinese Family

2021 ◽  
Vol 12 ◽  
Author(s):  
Cong Zhou ◽  
Yuanyuan Xiao ◽  
Hanbing Xie ◽  
Jing Wang ◽  
Shanling Liu
Keyword(s):  
Autosomal Recessive ◽  
Actin Binding ◽  
Chinese Family ◽  
Compound Heterozygous ◽  
Pathogenic Variants ◽  
Heterozygous Carriers ◽  
Compound Heterozygous Variants ◽  
And Function ◽  
Population Databases ◽  
Generation Sequencing

Autosomal recessive non-syndromic deafness-28 (DFNB28) is characterized by prelingual, profound sensorineural hearing loss (HL). The disease is related to variants of the TRIOBP gene. TRIO and F-actin binding protein (TRIOBP) plays crucial roles in modulating the assembly of the actin cytoskeleton and are responsible for the proper structure and function of stereocilia in the inner ear. This study aimed to identify pathogenic variants in a patient with HL. Genomic DNA obtained from a 33-year-old woman with HL was evaluated using a disease-targeted gene panel. Using next generation sequencing and bioinformatics analysis, we identified two novel TRIOBP c.1170delC (p.S391Pfs*488) and c.3764C > G (p.S1255*) variants. Both parents of the patient were heterozygous carriers of the gene. The two variants have not been reported in general population databases or published literature. The findings of this study will broaden the spectrum of pathogenic variants in the TRIOBP gene.

Clinical and Pathological Features of a Newborn With Compound Heterozygous ANKS6 Variants

2019 ◽  
Vol 23 (3) ◽  
pp. 235-239
Author(s):  
Sakil Kulkarni ◽  
Brooj Abro ◽  
Maria Laura Duque Lasio ◽  
Janis Stoll ◽  
Dorothy K Grange ◽  
...  
Keyword(s):  
Cardiac Failure ◽  
Renal Dysplasia ◽  
Cardiomyocyte Hypertrophy ◽  
Compound Heterozygous ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Genes Encoding ◽  
Cystic Renal Dysplasia ◽  
Cystic Renal Disease ◽  
Compound Heterozygous Variants

We report a term female infant born to nonconsanguineous parents who presented with renal failure at birth, hypothyroidism, cholestasis, and progressive cardiac dysfunction. Multigene next-generation sequencing panels for cholestasis, cardiomyopathy, and cystic renal disease did not reveal a unifying diagnosis. Whole exome sequencing revealed compound heterozygous pathogenic variants in ANKS6 (Ankyrin Repeat and Sterile Alpha Motif Domain Containing 6), which encodes a protein that interacts with other proteins of the Inv compartment of cilium ( NEK8, NPHP2/INVS, and NPHP3). ANKS6 has been shown to be important for early renal development and cardiac looping in animal models. Autopsy revealed cystic renal dysplasia and cardiomyocyte hypertrophy, disarray, and focal necrosis. Liver histology revealed cholestasis and centrilobular necrosis, which was likely a result of progressive cardiac failure. This is the first report of compound heterozygous variants in ANKS6 leading to a nephronopthisis-related ciliopathy-like phenotype. We conclude that pathogenic variants in ANKS6 may present early in life with severe renal and cardiac failure, similar to subjects with variants in genes encoding other proteins in the Inv compartment of the cilium.

scholarly journals Intragenic variants in the SMN1 gene determine the clinical phenotype in 5q spinal muscular atrophy

2020 ◽  
Vol 6 (5) ◽  
pp. e505
Author(s):  
Rodrigo de Holanda Mendonça ◽  
Ciro Matsui ◽  
Graziela Jorge Polido ◽  
André Macedo Serafim Silva ◽  
Leslie Kulikowski ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Copy Number ◽  
Clinical Phenotype ◽  
Muscular Atrophy ◽  
Large Population ◽  
Survival Motor Neuron ◽  
Compound Heterozygous ◽  
Pathogenic Variants ◽  
Exon 1 ◽  
Compound Heterozygous Variants

ObjectiveThe aim of the study was to report the proportion of homozygous and compound heterozygous variants in the survival motor neuron 1 (SMN1) gene in a large population of patients with spinal muscular atrophy (SMA) and to correlate the severity of the disease with the presence of specific intragenic variants in SMN1 and with the SMN2 copy number.MethodsFour hundred fifty Brazilian patients with SMA were included in a retrospective study, and clinical data were analyzed compared with genetic data; the SMN2 copy number was obtained by multiplex ligation-dependent probe amplification and pathogenic variants in SMN1 by next-generation sequencing.ResultsFour hundred two patients (89.3%) presented homozygous exon 7-SMN1 deletion, and 48 (10.7%) were compound heterozygous for the common deletion in one allele and a point mutation in the other allele. Recurrent variants in exons 3 and 6 (c.460C>T, c.770_780dup and c.734_735insC) accounted for almost 80% of compound heterozygous patients. Another recurrent pathogenic variant was c.5C>G at exon 1. Patients with c.770_780dup and c.734_735insC had a clinical phenotype correlated with SMN2 copy number, whereas the variants c.460C>T and c.5C>G determined a milder phenotype independently of the SMN2 copies.ConclusionsPatients with specific pathogenic variants (c.460C>T and c.5C>G) presented a milder phenotype, and the SMN2 copy number did not correlate with disease severity in this group.

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

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Niu Li ◽  
Yufei Xu ◽  
Yi Zhang ◽  
Guoqiang Li ◽  
Tingting Yu ◽  
...  
Keyword(s):  
Postnatal Growth ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
Atrioventricular Canal ◽  
Multiple Systems ◽  
Feeding Difficulties ◽  
Functional Studies ◽  
Pathogenic Variants ◽  
Compound Heterozygous Variants

Abstract 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.

scholarly journals Compound heterozygous inheritance of two novel COQ2 variants results in familial coenzyme Q deficiency

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Aliaa H. Abdelhakim ◽  
Avinash V. Dharmadhikari ◽  
Sara D. Ragi ◽  
Jose Ronaldo Lima de Carvalho ◽  
Christine L. Xu ◽  
...  
Keyword(s):  
Coenzyme Q ◽  
Clinical Manifestations ◽  
Missense Variant ◽  
Neurological Involvement ◽  
Cone Dystrophy ◽  
Compound Heterozygous ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Compound Heterozygous Variants ◽  
End Stage

Abstract Background Primary coenzyme Q10 deficiency is a rare disease that results in diverse and variable clinical manifestations. Nephropathy, myopathy and neurologic involvement are commonly associated, however retinopathy has also been observed with certain pathogenic variants of genes in the coenzyme Q biosynthesis pathway. In this report, we describe a novel presentation of the disease that includes nephropathy and retinopathy without neurological involvement, and which is the result of a compound heterozygous state arising from the inheritance of two recessive potentially pathogenic variants, previously not described. Materials and methods Retrospective report, with complete ophthalmic examination, multimodal imaging, electroretinography, and whole exome sequencing performed on a family with three affected siblings. Results We show that affected individuals in the described family inherited two heterozygous variants of the COQ2 gene, resulting in a frameshift variant in one allele, and a predicted deleterious missense variant in the second allele (c.288dupC,p.(Ala97Argfs*56) and c.376C > G,p.(Arg126Gly) respectively). Electroretinography results were consistent with rod-cone dystrophy in the affected individuals. All affected individuals in the family exhibited the characteristic retinopathy as well as end-stage nephropathy, without evidence of any neurological involvement. Conclusions We identified two novel compound heterozygous variants of the COQ2 gene that result in primary coenzyme Q deficiency. Targeted sequencing of coenzyme Q biosynthetic pathway genes may be useful in diagnosing oculorenal clinical presentations syndromes not explained by more well known syndromes (e.g., Senior-Loken and Bardet-Biedl syndromes).

Two Novel Mutations Cause Hereditary Antithrombin Deficiency in a Chinese Family

2019 ◽  
Vol 143 (3) ◽  
pp. 260-265
Author(s):  
Haiyue Zhang ◽  
Siqi Liu ◽  
Shasha Luo ◽  
Yanhui Jin ◽  
Lihong Yang ◽  
...  
Keyword(s):  
Frameshift Mutation ◽  
Gene Sequencing ◽  
Chinese Family ◽  
Compound Heterozygous ◽  
Sequencing Analysis ◽  
The Novel ◽  
Normal Range ◽  
Novel Mutations ◽  
Antithrombin Deficiency ◽  
At Deficiency

Objective: To study the molecular basis of hereditary antithrombin (AT) deficiency in a Chinese family. It will help us understand the pathogenesis of this type of disease. Method: AT activity (AT:A) and the AT antigen (AT:Ag) level were tested by chromogenic substrate and immunoturbidimetry, respectively. To identify the novel mutations, SERPINC1 gene sequencing was carried out. The possible impact of the mutations was analyzed by model and bioinformatic analyses. Results: AT:A and the AT:Ag level of the proband were 43% and 113 mg/L (normal range: 98–119% and 250–360 mg/L), respectively. Sequencing analysis revealed compound heterozygous mutations, including a frameshift mutation (c.318_319insT) resulting in Asn75stop and a missense mutation (c.922G>T) resulting in Gly276Cys. The bioinformatic and model analyses indicated that these mutations may disrupt the function and structure of the AT protein. Conclusion: We detected 2 novel heterozygous mutations (c.318_319insT and c.922G>T) in the proband, and these were associated with decreased AT:A.

A Novel 4.25kb Deletion in PAX6 in A Chinese Han Family with Congenital Aniridia Combined with Cataract and Nystagmus

2021 ◽  
Author(s):  
Tianwei Qian ◽  
Chong Chen ◽  
Caihua Li ◽  
Qiaoyun Gong ◽  
Kun Liu ◽  
...  
Keyword(s):  
Genetic Defect ◽  
Family Members ◽  
Anterior Segment ◽  
Chinese Family ◽  
The Novel ◽  
Slit Lamp ◽  
Heterozygous Deletion ◽  
Chinese Han ◽  
Normal People ◽  
Congenital Aniridia

Abstract Background: The aim of this study is to identify the genetic defect in a Chinese family with congenital aniridia combined with cataract and nystagmus.Methods: Complete ophthalmic examinations, including slit-lamp biomicroscopy, dilatedindirect ophthalmoscopy, anterior segment photography, and anterior segment optical coherence tomography (OCT) were performed. Blood samples were collected from all family members and genomic DNA was extracted. Genome sequencing was performed in all family members and Sanger sequencing was used to verify variant breakpoints.Results: All the thirteen members in this Chinese family, including seven patients and six normal people, were recruited in this study. The ophthalmic examination of affected patients in this family was consistent with congenital aniridia combined with cataract and nystagmus. A novel heterozygous deletion (NC_000011.10:g.31802307_31806556del) containing the 5’ region of PAX6 gene was detected that segregated with the disease. Conclusion: We detected a novel deletion in PAX6 responsible for congenital aniridia in the affected individuals of this Chinese family. The novel 4.25kb deletion in PAX6 gene of our study would further broaden the genetic defects of PAX6 associated with congenital aniridia.

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