scholarly journals Case Report: Compound Heterozygous Variants in MOCS3 Identified in a Chinese Infant With Molybdenum Cofactor Deficiency

2021 ◽  
Vol 12 ◽  
Author(s):  
Qi Tian ◽  
Yang Cao ◽  
Li Shu ◽  
Yongjun Chen ◽  
Ying Peng ◽  
...  
Keyword(s):  
Brain Mri ◽  
Genetic Diagnosis ◽  
Clinical Information ◽  
Molybdenum Cofactor ◽  
Compound Heterozygous ◽  
Causative Gene ◽  
Pathogenic Variants ◽  
First Case ◽  
Healthy Family ◽  
Compound Heterozygous Variants

Background: The molybdenum cofactor (Moco) deficiency in humans results in the inactivity of molybdenum-dependent enzymes and is caused by pathogenic variants in MOCS1 (Molybdenum cofactor synthesis 1), MOCS2 (Molybdenum cofactor synthesis 2), and GPHN (Gephyrin). These genes along with MOCS3 (Molybdenum cofactor synthesis 3) are involved in Moco biosynthesis and providing cofactors to Moco-dependent enzymes. Until now, there was no study to confirm that MOCS3 is a causative gene of Moco deficiency.Methods: Detailed clinical information was collected in the pedigree. The Whole-exome sequencing (WES) accompanied with Sanger sequencing validation were performed.Results: We described the clinical presentations of an infant, born to a non-consanguineous healthy family, diagnosed as having MOCS3 variants caused Moco deficiency and showing typical features of Moco deficiency including severe neurologic symptoms and cystic encephalomalacia in the brain MRI, resulting in neonatal death. Compound heterozygous variants in the MOCS3 gene were identified by WES. Positive sulfite and decreased levels of uric acid in plasma and urine were detected.Conclusion: To our knowledge, this is the first case of MOCS3 variants causing Moco deficiency. Our study may contribute to genetic diagnosis of Moco deficiency and future genetic counseling.

scholarly journals Bi-allelic variants in MTMR5/SBF1 cause Charcot-Marie-Tooth type 4B3 featuring mitochondrial dysfunction

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Beatrice Berti ◽  
Giovanna Longo ◽  
Francesco Mari ◽  
Stefano Doccini ◽  
Ilaria Piccolo ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Mitochondrial Dysfunction ◽  
Early Onset ◽  
Integrated Approach ◽  
Compound Heterozygous ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Pathogenic Variants ◽  
First Case ◽  
Spine Mri

Abstract Background Charcot-Marie-Tooth disease (CMT) type 4B3 (CMT4B3) is a rare form of genetic neuropathy associated with variants in the MTMR5/SBF1 gene. MTMR5/SBF1 is a pseudophosphatase predicted to regulate endo-lysosomal trafficking in tandem with other MTMRs. Although almost ubiquitously expressed, pathogenic variants primarily impact on the peripheral nervous system, corroborating the involvement of MTMR5/SBF1 and its molecular partners in Schwann cells-mediated myelinization. Case presentation We report a case of severe CMT4B3 characterized by early-onset motor and axonal polyneuropathy in an Italian child in absence of any evidence of brain and spine MRI abnormalities or intellectual disability and with a biochemical profile suggestive of mitochondrial disease. Using an integrated approach combining both NGS gene panels and WES analysis, we identified two novel compound heterozygous missense variants in MTMR5/SBF1 gene, p.R763H (c.2291G > A) and p.G1064E (c.3194G > A). Studies in muscle identified partial defects of oxidative metabolism. Conclusion We describe the first case of an early onset severe polyneuropathy with motor and axonal involvement, due to recessive variants in the MTMR5/SBF1 gene, with no evidence of brain and spine MRI abnormalities, intellectual disability, no clinical and neurophysiological evidences of distal sensory impairment, and rapid neuromuscular deterioration. This report suggests that MTMR5/SBF1 should be considered in cases of infantile-onset CMT with secondary mitochondrial dysfunction.

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.

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.

Prenatal genetic diagnosis of cranioectodermal dysplasia in a Polish family with compound heterozygous variants in WDR35

2020 ◽  
Vol 182 (10) ◽  
pp. 2417-2425
Author(s):  
Joanna Walczak‐Sztulpa ◽  
Anna Wawrocka ◽  
Beata Leszczynska ◽  
Boyana Mikulska ◽  
Heleen H. Arts ◽  
...  
Keyword(s):  
Genetic Diagnosis ◽  
Compound Heterozygous ◽  
Prenatal Genetic Diagnosis ◽  
Compound Heterozygous Variants

scholarly journals Clinical and genetic characterization of congenital hyperinsulinism in Spain

2016 ◽  
Vol 174 (6) ◽  
pp. 717-726 ◽  
Author(s):  
R Martínez ◽  
C Fernández-Ramos ◽  
A Vela ◽  
T Velayos ◽  
A Aguayo ◽  
...  
Keyword(s):  
Mutational Analysis ◽  
Genetic Diagnosis ◽  
Clinical Information ◽  
Severe Hypoglycemia ◽  
Compound Heterozygous ◽  
Congenital Hyperinsulinism ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Lower Blood ◽  
Design And Methods

Context Congenital hyperinsulinism (CHI) is a clinically and genetically heterogeneous disease characterized by severe hypoglycemia caused by inappropriate insulin secretion by pancreatic β-cells. Objective To characterize clinically and genetically CHI patients in Spain. Design and methods We included 50 patients with CHI from Spain. Clinical information was provided by the referring clinicians. Mutational analysis was carried out for KCNJ11, ABCC8, and GCK genes. The GLUD1, HNF4A, HNF1A, UCP2, and HADH genes were sequenced depending on the clinical phenotype. Results We identified the genetic etiology in 28 of the 50 CHI patients tested: 21 had a mutation in KATP channel genes (42%), three in GLUD1 (6%), and four in GCK (8%). Most mutations were found in ABCC8 (20/50). Half of these patients (10/20) were homozygous or compound heterozygous, with nine being unresponsive to diazoxide treatment. The other half had heterozygous mutations in ABCC8, six of them being unresponsive to diazoxide treatment and four being responsive to diazoxide treatment. We identified 22 different mutations in the KATP channel genes, of which ten were novel. Notably, patients with ABCC8 mutations were diagnosed earlier, with lower blood glucose levels and required higher doses of diazoxide than those without a genetic diagnosis. Conclusions Genetic analysis revealed mutations in 56% of the CHI patients. ABCC8 mutations are the most frequent cause of CHI in Spain. We found ten novel mutations in the KATP channel genes. The genetic diagnosis is more likely to be achieved in patients with onset within the first week of life and in those who fail to respond to diazoxide treatment.

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 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 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).

Sign in / Sign up

Export Citation Format

Share Document