Novel Pathogenic Mutations of FERMT1 in two Chinese Kindler Syndrome Families

2021 ◽  
Author(s):  
Min Li ◽  
Weisheng Li ◽  
Dan Zhu ◽  
Likui Lu ◽  
Jingliu Liu ◽  
...  
Keyword(s):  
Autosomal Recessive Disorder ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
Nonsense Mutations ◽  
Chinese Families ◽  
Kindler Syndrome ◽  
Pathogenic Mutations ◽  
Whole Exome ◽  
Palmoplantar Hyperkeratosis ◽  
Cigarette Paper

Abstract Background: Kindler syndrome (KNDLRS) is a very rare autosomal recessive disorder characterized by bullous poikiloderma with photosensitivity. Loss-of-function mutations in FERMT1, which located on chromosome 20p12.3, were responsible for KNDLRS. Numerous mutations in FERMT1 have been reported to be associated with KNDLRS. Results: The present study reported two Chinese KNDLRS families, and affected individuals from both families presented with poikiloderma, palmoplantar hyperkeratosis, and diffuse cigarette paper like atrophy on hands. Skin biopsy of the proband from family 2 showed atrophy of epidermis, hyperkeratosis, dilated blood vessels in upper dermis, and microbubbles at the dermis and epidermis junction. Medical Whole Exome Sequencing V4 combined with Sanger sequencing revealed mutations in FERMT1 with affected individuals. Compound heterozygous nonsense mutations (c.193C>T, c.277C>T) were found with family 1, and a homozygous frameshift mutation (c.220delC) was observed in family 2. According to the clinical features and genetic analysis, KNDLRS was diagnosed in two Chinese families. Conclusions: This study revealed two novel pathogenic mutations in FERMT1 that caused KNDLRS and briefly summarized all pathogenic mutations in FERMT1 that have been documented via the PubMed.

scholarly journals Rare Variants in Autophagy and Non-Autophagy Genes in Late-Onset Pompe Disease: Suggestions of Their Disease-Modifying Role in Two Italian Families

2021 ◽  
Vol 22 (7) ◽  
pp. 3625
Author(s):  
Filomena Napolitano ◽  
Giorgia Bruno ◽  
Chiara Terracciano ◽  
Giuseppina Franzese ◽  
Nicole Piera Palomba ◽  
...  
Keyword(s):  
Pompe Disease ◽  
Rare Variants ◽  
Clinical Symptoms ◽  
Late Onset ◽  
Respiratory Muscles ◽  
Autosomal Recessive Disorder ◽  
Compound Heterozygous ◽  
Enzyme Replacement ◽  
Whole Exome ◽  
Clinical Pictures

Pompe disease is an autosomal recessive disorder caused by a deficiency in the enzyme acid alpha-glucosidase. The late-onset form of Pompe disease (LOPD) is characterized by a slowly progressing proximal muscle weakness, often involving respiratory muscles. In LOPD, the levels of GAA enzyme activity and the severity of the clinical pictures may be highly variable among individuals, even in those who harbour the same combination of GAA mutations. The result is an unpredictable genotype–phenotype correlation. The purpose of this study was to identify the genetic factors responsible for the progression, severity and drug response in LOPD. We report here on a detailed clinical, morphological and genetic study, including a whole exome sequencing (WES) analysis of 11 adult LOPD siblings belonging to two Italian families carrying compound heterozygous GAA mutations. We disclosed a heterogeneous pattern of myopathic impairment, associated, among others, with cardiac defects, intracranial vessels abnormality, osteoporosis, vitamin D deficiency, obesity and adverse response to enzyme replacement therapy (ERT). We identified deleterious variants in the genes involved in autophagy, immunity and bone metabolism, which contributed to the severity of the clinical symptoms observed in the LOPD patients. This study emphasizes the multisystem nature of LOPD and highlights the polygenic nature of the complex phenotype disclosed in these patients.

scholarly journals Biallelic DAB1 Variants Are Associated With Mild Lissencephaly and Cerebellar Hypoplasia

2021 ◽  
Vol 7 (2) ◽  
pp. e558
Author(s):  
Daphne J. Smits ◽  
Rachel Schot ◽  
Martina Wilke ◽  
Marjon van Slegtenhorst ◽  
Marie Claire Y. de Wit ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Splice Variants ◽  
Brain Mri ◽  
Cerebellar Vermis ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
Functional Studies ◽  
Pathogenic Variants ◽  
Whole Exome

ObjectiveWe aimed to identify pathogenic variants in a girl with epilepsy, developmental delay, cerebellar ataxia, oral motor difficulty, and structural brain abnormalities with the use of whole-exome sequencing.MethodsWhole-exome trio analysis and molecular functional studies were performed in addition to the clinical findings and neuroimaging studies.ResultsBrain MRI showed mild pachygyria, hypoplasia of the cerebellar vermis, and abnormal foliation of the cerebellar vermis, suspected for a variant in one of the genes of the Reelin pathway. Trio whole-exome sequencing and additional functional studies were performed to identify the pathogenic variants. Trio whole-exome sequencing revealed compound heterozygous splice variants in DAB1, both affecting the highly conserved functional phosphotyrosine-binding domain. Expression studies in patient-derived cells showed loss of normal transcripts, confirming pathogenicity.ConclusionsWe conclude that these variants are very likely causally related to the cerebral phenotype and propose to consider loss-of-function DAB1 variants in patients with RELN-like cortical malformations.

scholarly journals Heme oxygenase-1 deficiency presenting with interstitial lung disease and hemophagocytic flares

2020 ◽  
Author(s):  
Alice S. Chau ◽  
Bonnie L. Cole ◽  
Jason S. Debley ◽  
Kabita Nanda ◽  
Aaron B.I. Rosen ◽  
...  
Keyword(s):  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Heme Oxygenase ◽  
Autosomal Recessive Disorder ◽  
Clinical Findings ◽  
Heme Oxygenase 1 ◽  
Compound Heterozygous ◽  
Biliverdin Reductase ◽  
Frame Shift ◽  
Whole Exome

Abstract Background Heme oxygenase-1 (HMOX1) catalyzes the metabolism of heme into carbon monoxide, ferrous iron, and biliverdin. Through biliverdin reductase, biliverdin becomes bilirubin. HMOX1 -deficiency is an exceedingly rare autosomal recessive disorder with hallmark features of direct antibody negative hemolytic anemia with normal bilirubin, hyperinflammation and features indicating hemophagocytosis lymphohistiocytosis. Clinical findings have included asplenia, nephritis, hepatitis, and evidence of vasculitis. Pulmonary features and evaluation of the immune response have been limited. Results Here, we present the fifth reported case in literature of a young boy who remarkably also presented with chronic respiratory failure due to nonspecific interstitial pneumonia in addition to infection-triggered recurrent hyperinflammatory flares notable for hemolysis without hyperbilirubinemia, immunodeficiency, hepatomegaly with mild transaminitis, asplenia, leukocytosis, thrombocytosis, joint pain and features of macrophage activation with negative autoimmune serologies. Lung biopsy revealed cholesterol granulomas. He was found post-mortem by whole exome sequencing to have a compound heterozygous paternal frame shift a paternal frame shift HMOX1 c.264delCTGG (p.L89Sfs*24) and maternal splice donor HMOX1 (c.636+2 T>A) consistent with HMOX1 deficiency. Western blot analysis confirmed lack of HMOX1 protein upon oxidant stimulation of the patient cells. Conclusions Here, we describe a phenotype expansion for HMOX1-deficiency to include not only asplenia and hepatomegaly, but also interstitial lung disease with cholesterol granulomas and inflammatory flares with hemophagocytosis present in the bone marrow.

3-M syndrome – a primordial short stature disorder with novel CUL7 mutation in two Indian patients

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Radha Rama Devi Akella
Keyword(s):  
Short Stature ◽  
Autosomal Recessive ◽  
Genetic Diagnosis ◽  
Autosomal Recessive Disorder ◽  
Missense Variant ◽  
Postnatal Growth ◽  
Compound Heterozygous ◽  
Case Presentation ◽  
Whole Exome ◽  
Heterozygous Variant

Abstract Objective To evaluate the cause of short stature in children. Case presentation Two children with suspected skeletal dysplasia and short stature were evaluated. Conclusions The 3-M syndrome is a primordial growth disorder manifesting severe postnatal growth restriction, skeletal anomalies and prominent fleshy heels. The 3-M syndrome is a genetically heterogeneous disorder and the phenotype is similar. This is a rare autosomal recessive disorder with normal intellect. Two affected children have been identified by whole-exome sequencing. One patient harboured a compound heterozygous variant and the other was a homozygous missense variant. The genetic diagnosis helped in counselling the families and facilitated prenatal diagnosis in one (case 1) family.

scholarly journals Identification of DNAH6 mutations in infertile men with multiple morphological abnormalities of the sperm flagella

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Chaofeng Tu ◽  
Hongchuan Nie ◽  
Lanlan Meng ◽  
Shimin Yuan ◽  
Wenbin He ◽  
...  
Keyword(s):  
Compound Heterozygous ◽  
Missense Mutations ◽  
Transmission Electron Microscopy Analysis ◽  
Chinese Families ◽  
Morphological Abnormalities ◽  
Recessive Mutations ◽  
Transmission Electron ◽  
Whole Exome ◽  
Electron Microscopy Analysis ◽  
Reproductive Counseling

Abstract Male infertility due to spermatogenesis defects affects millions of men worldwide. However, the genetic etiology of the vast majority remains unclear. Here we describe three men with primary infertility due to multiple morphological abnormalities of the sperm flagella (MMAF) from two unrelated Han Chinese families. We performed whole-exome sequencing (WES) and Sanger sequencing on the proband of family 1, and found that he carried novel compound heterozygous missense mutations in dynein axonemal heavy chain 6 (DNAH6) that resulted in the substitution of a conserved amino acid residue and co-segregated with the MMAF phenotype in this family. Papanicolaou staining and transmission electron microscopy analysis revealed morphological and ultrastructural abnormalities in the sperm flagella in carriers of these genetic variants. Immunostaining experiments showed that DNAH6 was localized in the sperm tail. This is the first report identifying novel recessive mutations in DNAH6 as a cause of MMAF. These findings expand the spectrum of known MMAF mutations and phenotypes and provide information that can be useful for genetic and reproductive counseling of MMAF patients.

scholarly journals Identification and Splicing Characterization of Novel TMC6 and TMC8 Variants Associated With Epidermodysplasia Verruciformis in Three Chinese Families

2021 ◽  
Vol 12 ◽  
Author(s):  
Rongrong Wang ◽  
Jiawei Liu ◽  
Xueting Yang ◽  
Xiaerbati Habulieti ◽  
Xue Yu ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Epidermodysplasia Verruciformis ◽  
Compound Heterozygous ◽  
Chinese Families ◽  
Qrt Pcr ◽  
Skin Cancers ◽  
Whole Exome ◽  
Heterozygous Variant ◽  
Nonsense Mediated Mrna Decay

Background: Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by abnormal susceptibility to human beta papillomavirus infections and a particular propensity to develop non-melanoma skin cancers (NMSCs). The majority of EV cases are caused by biallelic null variants in TMC6, TMC8, and CIB1. This study aimed to identify disease-causing variants in three Chinese families with EV and to elucidate their molecular pathogenesis.Methods: Genomic DNA from the probands of three EV families was analyzed by whole-exome sequencing (WES). cDNA sequencing was performed to investigate abnormal splicing of the variants. Quantitative RT-PCR (qRT-PCR) was conducted to quantify the mRNA expression of mutant TMC6 and TMC8.Results: Whole-exome sequencing identified two novel homozygous variants (c.2278-2A > G in TMC6 and c.559G > A in TMC8) in families 1 and 2, respectively. In family 3, WES revealed a recurrent and a novel compound heterozygous variant, c.559G > A and c.1389G > A, in TMC8. The c.2278-2A > G TMC6 variant led to the skipping of exon 19 and resulted in premature termination at codon 776. Subsequent qRT-PCR revealed that the aberrantly spliced transcript was partly degraded. Notably, the TMC8 c.559G > A variant created a novel acceptor splice site at c.561 and yielded three different aberrant transcripts. qRT-PCR revealed that most of the mutant transcripts were degraded via nonsense-mediated mRNA decay (NMD).Conclusion: We identified three novel disease-causing variants in TMC6 or TMC8 in three Chinese families with EV. The EV phenotypes of the three patients were due to a reduction in TMC6 or TMC8. Our findings expand the genetic causes of EV in the Chinese population.

Webb–Dattani Syndrome: Report of a Saudi Arabian Family with a Novel Homozygous Mutation in the ARNT2 Gene

2018 ◽  
Vol 17 (02) ◽  
pp. 071-076 ◽  
Author(s):  
Nouriya Abbas Al-Sannaa ◽  
Alexander Pepler ◽  
Hind Y. Al-Abdulwahed ◽  
Sami I. Al-Majed ◽  
Rifat F. Abdi ◽  
...  
Keyword(s):  
Saudi Arabian ◽  
Autosomal Recessive Disorder ◽  
Cortical Blindness ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Homozygous Mutation ◽  
Loss Of Function ◽  
Whole Exome ◽  
Retinal Examination

AbstractWebb–Dattani syndrome (WEDAS) is an autosomal recessive disorder caused by mutation in the ARNT2 gene characterized by frontotemporal hypoplasia, globally delayed development, and pituitary and hypothalamic insufficiency. The condition is reported to be associated with consanguinity and with Saudi Arabian ancestry. Here we describe a family of three affected siblings born to healthy second cousin parents of Saudi Arabian ancestry. The children presented at 3 months of age with congenital central hypotonia and hypoventilation, central diabetes insipidus, multiple pituitary hormone deficiency, severe developmental delay, acquired microcephaly, cortical blindness with normal retinal examination, seizures, and gastroesophageal reflux. Whole exome sequencing detected a homozygous unclear variant (c.378C>T; p.G126G) in the ARNT2 gene in both the affected twins. According to splice prediction programs, this variant results in the creation of a cryptic donor splice site, possibly leading to a loss of function. These data support the role of the detected mutation in the ARNT2 gene in causing the described phenotype.

scholarly journals Biallelic mutations in CFAP65 lead to severe asthenoteratospermia due to acrosome hypoplasia and flagellum malformations

2019 ◽  
Vol 56 (11) ◽  
pp. 750-757 ◽  
Author(s):  
Weili Wang ◽  
Chaofeng Tu ◽  
Hongchuan Nie ◽  
Lanlan Meng ◽  
Yong Li ◽  
...  
Keyword(s):  
Sperm Morphology ◽  
Mutation Screening ◽  
Compound Heterozygous ◽  
Obstructive Azoospermia ◽  
Control Cohort ◽  
Chinese Families ◽  
Whole Exome ◽  
Compound Heterozygous Mutations ◽  
Biallelic Mutations ◽  
Immotile Spermatozoa

BackgroundThe genetic causes for most male infertility due to severe asthenozoospermia remain unclear.ObjectiveOur objective was to identify unknown genetic factors in 47 patients with severe asthenozoospermia from 45 unrelated Chinese families.MethodsWe performed whole exome sequencing of 47 individuals with severe asthenozoospermia from 45 unrelated families. Mutation screening was performed in a control cohort of 637 individuals, including 219 with oligoasthenospermia, 195 with non-obstructive azoospermia and 223 fertile controls. Ultrastructural and immunostaining analyses of patients’ spermatozoa were performed to characterise the effect of variants.ResultsOne homozygous non-sense mutation (NM_194302, c.G5341T:p.E1781X), two compound heterozygous mutations (c.C2284T:p.R762X and c.1751delC:p.P584fs) and two compound heterozygous mutations (c.5714_5721del:p.L1905fs and c.C3021A:p.N1007K) were identified in CFAP65 of three individuals with completely immotile spermatozoa, respectively. No biallelic deleterious variants of CFAP65 were detected in the control cohort of 637 individuals. Ultrastructural and immunostaining analyses of spermatozoa from two patients showed highly aberrant sperm morphology with severe defects such as acrosome hypoplasia, disruption of the mitochondrial sheath and absence of the central pair complex.ConclusionTo the best of our knowledge, we are the first to report that CFAP65 mutations may cause spermatozoa to be completely immotile.

scholarly journals Whole Exome Sequencing Identifies a Novel and a Recurrent Mutation inBBS2Gene in a Family with Bardet-Biedl Syndrome

2015 ◽  
Vol 2015 ◽  
pp. 1-5 ◽  
Author(s):  
Yong Mong Bee ◽  
Mayank Chawla ◽  
Yi Zhao
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Novel Mutation ◽  
Direct Sequencing ◽  
Autosomal Recessive Disorder ◽  
The Novel ◽  
Nonsense Mutations ◽  
Bardet Biedl Syndrome ◽  
Next Generation Sequencing Technology ◽  
Whole Exome

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder known to be caused by mutations in at least 19 BBS genes. We report the genetic analysis of a patient with indisputable features of BBS including cardinal features such as postaxial polydactyly, retinitis pigmentosa, obesity, and kidney failure. Taking advantage of next-generation sequencing technology, we applied whole exome sequencing (WES) with Sanger direct sequencing to the proband and her unaffected mother. A pair of heterozygous nonsense mutations inBBS2gene was identified in the proband, one being novel and the other recurrent. The novel mutation, p.Y644X, resides in exon 16 and was also found in the heterozygous state in the mother. This mutation is not currently found in the dsSNP and 1000 Genome SNP databases and is predicted to be disease causing byin silicoanalysis. This study highlights the potential for a rapid and precise detection of disease causing gene using WES in genetically heterogeneous disorders such as BBS.

scholarly journals Novel Gross Deletion Mutations in NTRK1 Gene Associated With Congenital Insensitivity to Pain With Anhidrosis

2021 ◽  
Vol 9 ◽  
Author(s):  
Lulu Li ◽  
Chao Jia ◽  
Yue Tang ◽  
Yuanyuan Kong ◽  
Yaofang Xia ◽  
...  
Keyword(s):  
Autosomal Recessive Disorder ◽  
Recurrent Fever ◽  
Tyrosine Kinase Receptor ◽  
Compound Heterozygous ◽  
Chinese Families ◽  
Alu Elements ◽  
Deletion Mutations ◽  
Congenital Insensitivity ◽  
Congenital Insensitivity To Pain ◽  
Insensitivity To Pain

Background: Congenital insensitivity to pain with anhidrosis (CIPA) is a rare inherited autosomal recessive disorder characterized by insensitivity to noxious stimuli, anhidrosis, recurrent fever, and intellectual disability. CIPA is mainly caused by mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1). This study aims to identify pathogenic mutations underlying CIPA in two unrelated Chinese families.Methods: DNA was extracted from blood samples of patients and their available family members and subjected to whole exome sequencing (WES). Real-time PCR (qPCR), Gap-PCR, and Sanger sequencing were applied to verify the identified variants.Result: We found novel compound gross deletion mutations [exon1-6 del (g.1-1258_10169del); exon5-7 del (g.6995_11999del)] of NTRK1 (MIM 191315) gene in family 1 and the compound heterozygous mutations [c.851-33T>A; exon5-7 del (g.6995_11999del)] in family 2. Interestingly, we discovered the intragenic novel gross deletion [exon5-7 del (g.6995_11999del)] mediated by recombination between Alu elements.Conclusions: The present study highlights two rare gross deletion mutations in the NTRK1 gene associated with CIPA in two unrelated Chinese families. The deletion of exon1-6 (g.1-1258_10169del) is thought to be the largest NTRK1 deletion reported to date. Our findings expand the mutation spectrum of NTRK1 mutations in the Chinese and could be useful for prenatal interventions and more precise pharmacological treatments to patients. WES conducted in our study is a convenient and useful tool for clinical diagnosis of CIPA and other associated disorders.

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