scholarly journals A Novel GEMIN4 Variant in a Consanguineous Family Leads to Neurodevelopmental Impairment with Severe Microcephaly, Spastic Quadriplegia, Epilepsy, and Cataracts

Genes ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 92
Author(s):  
Hesham Aldhalaan ◽  
Albandary AlBakheet ◽  
Sarah AlRuways ◽  
Nouf AlMutairi ◽  
Maha AlNakiyah ◽  
...  
Keyword(s):  
Clinical Features ◽  
Phenotypic Characteristics ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Spastic Quadriplegia ◽  
Novel Variant ◽  
Sanger Sequence ◽  
Saudi Family ◽  
Neurodevelopmental Impairment ◽  
Renal Abnormalities

Pathogenic variants in GEMIN4 contribute to a hereditary disorder characterized by neurodevelopmental features, microcephaly, cataracts, and renal abnormalities (known as NEDMCR). To date, only two homoallelic variations have been linked to the disease. Moreover, clinical features associated with the variants have not been fully elucidated yet. Here, we identified a novel variant in GEMIN4 (NM_015721:exon2:c.440A>G:p.His147Arg) in two siblings from a consanguineous Saudi family by using whole exome sequencing followed by Sanger sequence verification. We comprehensively investigated the patients’ clinical features, including brain imaging and electroencephalogram findings, and compared their phenotypic characteristics with those of previously reported cases. In silico prediction and structural modeling support that the p.His147Arg variant is pathogenic.

scholarly journals Identification and characterization of NF1 and non-NF1 congenital pseudarthrosis of the tibia based on germline NF1 variants: genetic and clinical analysis of 75 patients

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Guanghui Zhu ◽  
Yu Zheng ◽  
Yaoxi Liu ◽  
An Yan ◽  
Zhengmao Hu ◽  
...  
Keyword(s):  
Clinical Features ◽  
De Novo ◽  
Bone Fractures ◽  
Neurofibromatosis Type ◽  
Clinical Analysis ◽  
Congenital Pseudarthrosis ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
New Perspective

Abstract Background Congenital pseudarthrosis of the tibia (CPT) is a rare disease. Some patients present neurofibromatosis type 1 (NF1), while some others do not manifest NF1 (non-NF1). The etiology of CPT, particularly non-NF1 CPT, is not well understood. Here we screened germline variants of 75 CPT cases, including 55 NF1 and 20 non-NF1. Clinical data were classified and analyzed based on NF1 gene variations to investigate the genotype-phenotype relations of the two types of patients. Results Using whole-exome sequencing and Multiplex Ligation-Dependent Probe Amplification, 44 out of 55 NF1 CPT patients (80.0%) were identified as carrying pathogenic variants of the NF1 gene. Twenty-five variants were novel; 53.5% of variants were de novo, and a higher proportion of their carriers presented bone fractures compared to inherited variant carriers. No NF1 pathogenic variants were found in all 20 non-NF1 patients. Clinical features comparing NF1 CPT to non-NF1 CPT did not show significant differences in bowing or fracture onset, lateralization, tissue pathogenical results, abnormality of the proximal tibial epiphysis, and follow-up tibial union after surgery. A considerably higher proportion of non-NF1 patients have cystic lesion (Crawford type III) and used braces after surgery. Conclusions We analyzed a large cohort of non-NF1 and NF1 CPT patients and provided a new perspective for genotype-phenotype features related to germline NF1 variants. Non-NF1 CPT in general had similar clinical features of the tibia as NF1 CPT. Germline NF1 pathogenic variants could differentiate NF1 from non-NF1 CPT but could not explain the CPT heterogeneity of NF1 patients. Our results suggested that non-NF1 CPT was probably not caused by germline NF1 pathogenic variants. In addition to NF1, other genetic variants could also contribute to CPT pathogenesis. Our findings would facilitate the interpretation of NF1 pathogenic variants in CPT genetic counseling.

scholarly journals Three Novel Variants of CEP290 and CC2D2DA and a Link Between ZNF77 and SHH Signaling Pathway Are Found in Two Meckel-Gruber Syndrome Fetuses

2022 ◽  
Author(s):  
Zhidan Hong ◽  
Xuanyi He ◽  
Fang Yu ◽  
Huanyu Liu ◽  
Xiaoli Zhang ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Pathological Examination ◽  
Compound Heterozygous ◽  
Over Expression ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
The Family ◽  
Novel Variants ◽  
Novel Variant ◽  
Missed Diagnosis

AbstractMeckel-Gruber syndrome (MKS) is a rare lethal autosomal recessive inherited disorder. Missed diagnosis might happen in clinical works due to an unclear genotype–phenotype correlation. We analyzed two families visiting our center; the parents are normal; each of the family aborted a fetus at 12WG. Following ultrasonography and pathological examination, both were diagnosed as MKS. Whole exome sequencing identified a compound heterozygous of two novel variants of CEP290 and a heterozygous of a novel variant of CC2D2A. Frameshift mutations in ZNF77 were also detected. Western blot analyzing whole-brain tissue showed that the expression of ZNF77, CC2D2A, and CEP290 was enhanced. HEK293T transfected with over-expression wildtype/mutated ZNF77 plasmid showed that SHH was increased in wildtype ZNF77 cells, while SHH and CC2D2A were increased in mutated ZNF77 cells. Our research provided two novel pathogenic variants of CEP290 and CC2D2A and suggested that ZNF77 might promote the expression of CC2D2A and regulate the amount of SHH.

scholarly journals A novel variant of IHH in a Chinese family with brachydactyly type 1

2019 ◽  
Author(s):  
Qi Yang ◽  
Jin Wang ◽  
Xiaoxian Tian ◽  
Fei Chen ◽  
Jing Lan ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Missense Variant ◽  
Chinese Family ◽  
Indian Hedgehog ◽  
Autosomal Dominant Disorder ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Novel Variant ◽  
Active Fragment

Abstract Brachydactyly type A1(BDA-1) is an autosomal dominant disorder which is caused by heterozygous pathogenic variants in a specific region of the N-terminal active fragment of Indian Hedgehog ( IHH ). The disorder is mainly characterized by shortening or missing of the middle phalanges. The following study revealed a novel heterozygous missense variant c.299A>G (p.D100G) at the mutational hotspot of IHH gene after performing whole-exome sequencing in the proband of a Chinese family with BDA-1. The variant co-segregated with BDA-1 in the pedigree, showed 100% penetrance for phalange phenotype with variable expressivity. This finding expanded the variants on IHH gene which contribute to the cause of BDA-1.

scholarly journals Myoclonic status epilepticus and cerebellar hypoplasia associated with a novel variant in the GRIA3 gene

Neurogenetics ◽  
2021 ◽  
Author(s):  
Berardo Rinaldi ◽  
Yu-Han Ge ◽  
Elena Freri ◽  
Arianna Tucci ◽  
Tiziana Granata ◽  
...  
Keyword(s):  
Causative Role ◽  
Cerebellar Syndrome ◽  
Pathogenic Variants ◽  
Healthy Mother ◽  
Whole Exome ◽  
The Family ◽  
Novel Variant ◽  
Gene Maps ◽  
Index Subject

AbstractAMPA-type glutamate receptors (AMPARs) are postsynaptic ionotropic receptors which mediate fast excitatory currents. AMPARs have a heterotetrameric structure, variably composed by the four subunits GluA1-4 which are encoded by genes GRIA1-4. Increasing evidence support the role of pathogenic variants in GRIA1-4 genes as causative for syndromic intellectual disability (ID). We report an Italian pedigree where some male individuals share ID, seizures and facial dysmorphisms. The index subject was referred for severe ID, myoclonic seizures, cerebellar signs and short stature. Whole exome sequencing identified a novel variant in GRIA3, c.2360A > G, p.(Glu787Gly). The GRIA3 gene maps to chromosome Xq25 and the c.2360A > G variant was transmitted by his healthy mother. Subsequent analysis in the family showed a segregation pattern compatible with the causative role of this variant, further supported by preliminary functional insights. We provide a detailed description of the clinical evolution of the index subjects and stress the relevance of myoclonic seizures and cerebellar syndrome as cardinal features of his presentation.

scholarly journals Identification of a Novel Variant of ARHGAP29 in a Chinese Family with Nonsyndromic Cleft Lip and Palate

2020 ◽  
Vol 2020 ◽  
pp. 1-6
Author(s):  
Jian-Xia Tang ◽  
Xiang-Shui Xiao ◽  
Kai Wang ◽  
Jie-Yuan Jin ◽  
Liang-Liang Fan ◽  
...  
Keyword(s):  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Genetic Diagnosis ◽  
Missense Variant ◽  
Bioinformatic Analysis ◽  
Chinese Family ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Novel Variant ◽  
Development Methods

Background. Cleft lip with or without cleft palate (CL/P) is the most common facial birth defect, with a worldwide incidence of 1 in 700-1000 live births. CL/P can be divided into syndromic CL/P (SCL/P) and nonsyndromic CL/P (NSCL/P). Genetic factors are an important component to the etiology of NSCL/P. ARHGAP29, one of the NSCL/P disease-causing genes, mediates the cyclical regulation of small GTP binding proteins such as RhoA and plays an essential role in cellular shape, proliferation, and craniofacial development. Methods. The present study investigated a Chinese family with NSCL/P and explored potential pathogenic variants using whole-exome sequencing (WES). Variants were screened and filtered through bioinformatic analysis and prediction of variant pathogenicity. Cosegregation was subsequently conducted. Results. We identified a novel heterozygous missense variant of ARHGAP29 (c.2615C > T, p.A872V) in a Chinese pedigree with NSCL/P. Conclusion. We detected the disease-causing variant in this NSCL/P family. Our identification expands the genetic spectrum of ARHGAP29 and contributes to novel approaches to the genetic diagnosis and counseling of CL/P families.

scholarly journals A novel variant of IHH in a Chinese family with brachydactyly type 1

2020 ◽  
Author(s):  
Qi Yang ◽  
Jin Wang ◽  
Xiaoxian Tian ◽  
Fei Chen ◽  
Jing Lan ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Missense Variant ◽  
Chinese Family ◽  
Indian Hedgehog ◽  
Autosomal Dominant Disorder ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Novel Variant ◽  
Active Fragment

Abstract Brachydactyly type A1(BDA-1) is an autosomal dominant disorder which is caused by heterozygous pathogenic variants in a specific region of the N-terminal active fragment of Indian Hedgehog ( IHH ). The disorder is mainly characterized by shortening or missing of the middle phalanges. The following study revealed a novel heterozygous missense variant c.299A>G (p.D100G) at the mutational hotspot of IHH gene after performing whole-exome sequencing in the proband of a Chinese family with BDA-1. The variant co-segregated with BDA-1 in the pedigree, showed 100% penetrance for phalange phenotype with variable expressivity. This finding expanded the variants on IHH gene which contribute to the cause of BDA-1.

scholarly journals Contribution of SLC22A12 on hypouricemia and its clinical significance for screening purposes

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Do Hyeon Cha ◽  
Heon Yung Gee ◽  
Raul Cachau ◽  
Jong Mun Choi ◽  
Daeui Park ◽  
...  
Keyword(s):  
Genetic Diagnosis ◽  
Kidney Injury ◽  
Genetic Identification ◽  
Diagnostic Screening ◽  
Renal Hypouricemia ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Causal Variants ◽  
Coding Variants ◽  
Independent Cohort

Abstract Differentiating between inherited renal hypouricemia and transient hypouricemic status is challenging. Here, we aimed to describe the genetic background of hypouricemia patients using whole-exome sequencing (WES) and assess the feasibility for genetic diagnosis using two founder variants in primary screening. We selected all cases (N = 31) with extreme hypouricemia (<1.3 mg/dl) from a Korean urban cohort of 179,381 subjects without underlying conditions. WES and corresponding downstream analyses were performed for the discovery of rare causal variants for hypouricemia. Two known recessive variants within SLC22A12 (p.Trp258*, pArg90His) were identified in 24 out of 31 subjects (77.4%). In an independent cohort, we identified 50 individuals with hypouricemia and genotyped the p.Trp258* and p.Arg90His variants; 47 of the 50 (94%) hypouricemia cases were explained by only two mutations. Four novel coding variants in SLC22A12, p.Asn136Lys, p.Thr225Lys, p.Arg284Gln, and p.Glu429Lys, were additionally identified. In silico studies predict these as pathogenic variants. This is the first study to show the value of genetic diagnostic screening for hypouricemia in the clinical setting. Screening of just two ethnic-specific variants (p.Trp258* and p.Arg90His) identified 87.7% (71/81) of Korean patients with monogenic hypouricemia. Early genetic identification of constitutive hypouricemia may prevent acute kidney injury by avoidance of dehydration and excessive exercise.

scholarly journals Whole-exome sequencing with targeted analysis and epilepsy after acute symptomatic neonatal seizures

2021 ◽  
Author(s):  
Adam L. Numis ◽  
Gilberto da Gente ◽  
Elliott H. Sherr ◽  
Hannah C. Glass
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
List Type ◽  
Sequencing Analysis ◽  
Neonatal Seizures ◽  
Pathogenic Variants ◽  
Targeted Analysis ◽  
Whole Exome ◽  
Epilepsy Gene

Abstract Background The contribution of pathogenic gene variants with development of epilepsy after acute symptomatic neonatal seizures is not known. Methods Case–control study of 20 trios in children with a history of acute symptomatic neonatal seizures: 10 with and 10 without post-neonatal epilepsy. We performed whole-exome sequencing (WES) and identified pathogenic de novo, transmitted, and non-transmitted variants from established and candidate epilepsy association genes and correlated prevalence of these variants with epilepsy outcomes. We performed a sensitivity analysis with genes associated with coronary artery disease (CAD). We analyzed variants throughout the exome to evaluate for differential enrichment of functional properties using exploratory KEGG searches. Results Querying 200 established and candidate epilepsy genes, pathogenic variants were identified in 5 children with post-neonatal epilepsy yet in only 1 child without subsequent epilepsy. There was no difference in the number of trios with non-transmitted pathogenic variants in epilepsy or CAD genes. An exploratory KEGG analysis demonstrated a relative enrichment in cell death pathways in children without subsequent epilepsy. Conclusions In this pilot study, children with epilepsy after acute symptomatic neonatal seizures had a higher prevalence of coding variants with a targeted epilepsy gene sequencing analysis compared to those patients without subsequent epilepsy. Impact We performed whole-exome sequencing (WES) in 20 trios, including 10 children with epilepsy and 10 without epilepsy, both after acute symptomatic neonatal seizures. Children with post-neonatal epilepsy had a higher burden of pathogenic variants in epilepsy-associated genes compared to those without post-neonatal epilepsy. Future studies evaluating this association may lead to a better understanding of the risk of epilepsy after acute symptomatic neonatal seizures and elucidate molecular pathways that are dysregulated after brain injury and implicated in epileptogenesis.

scholarly journals Combination of Novel c.3484G> T/p.Glu162Ter Variant in ABCB11 and c.208G> A/p.Asp70Asn Variant in ATP8B1 Are Associated with Severe Symptoms in Progressive Family Intrahepatic Cholestasis

2020 ◽  
Vol 09 (04) ◽  
pp. 285-288
Author(s):  
Mervan Bekdas ◽  
Guray Can ◽  
Recep Eroz ◽  
Selma Erdogan Duzcu
Keyword(s):  
Intrahepatic Cholestasis ◽  
Autosomal Recessive ◽  
Autosomal Recessive Disease ◽  
Bile Secretion ◽  
Peripheral Blood Sample ◽  
Portal Fibrosis ◽  
Traditional Treatment ◽  
Pathogenic Variants ◽  
Chronic Cholestasis ◽  
Whole Exome

AbstractProgressive family intrahepatic cholestasis (PFIC) is an autosomal recessive disease that causes chronic cholestasis. It is associated with pathogenic variants in genes that encode proteins involved in bile secretion to canaliculus from hepatocytes. In this study, we present a 16-year-old boy who presented with severe pruritus and cholestatic jaundice. All possible infectious etiologies were negative. A liver biopsy was consistent with intrahepatic cholestasis and portal fibrosis. DNA was isolated from a peripheral blood sample, and whole exome sequencing was performed. A novel c.3484G > T/p.Glu162Ter variant in the ABCB11 gene and a c.208G> A/p.Asp70Asn variant in the ATP8B1 gene were detected. Despite traditional treatment, the patient's recurrent severe symptoms did not improve. The patient was referred for a liver transplantation. This novel c.3484G > T/p.Glu162Ter variant is associated with a severe and recurrent presentation, and the two compound variants could explain the severity of PFIC.

RHOBTB2 p.Arg511Trp Mutation in Early Infantile Epileptic Encephalopathy-64: Review and Case Report

2021 ◽  
Author(s):  
J Fonseca ◽  
C Melo ◽  
C Ferreira ◽  
M Sampaio ◽  
R Sousa ◽  
...  
Keyword(s):  
Case Report ◽  
Intellectual Disability ◽  
Status Epilepticus ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Epileptic Encephalopathy ◽  
Btb Domain ◽  
Pathogenic Variants ◽  
Severe Intellectual Disability ◽  
Whole Exome

AbstractEarly infantile epileptic encephalopathy-64 (EIEE 64), also called RHOBTB2-related developmental and epileptic encephalopathy (DEE), is caused by heterozygous pathogenic variants (EIEE 64; MIM#618004) in the Rho-related BTB domain-containing protein 2 (RHOBTB2) gene. To date, only 13 cases with RHOBTB2-related DEE have been reported. We add to the literature the 14th case of EIEE 64, identified by whole exome sequencing, caused by a heterozygous pathogenic variant in RHOBTB2 (c.1531C > T), p.Arg511Trp. This additional case supports the main features of RHOBTB2-related DEE: infantile-onset seizures, severe intellectual disability, impaired motor functions, postnatal microcephaly, recurrent status epilepticus, and hemiparesis after seizures.

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