scholarly journals Lipoyltransferase 1 Gene Defect Resulting in Fatal Lactic Acidosis in Two Siblings

2016 ◽  
Vol 2016 ◽  
pp. 1-4 ◽  
Author(s):  
Véronique Taché ◽  
Liga Bivina ◽  
Sophie White ◽  
Jeffrey Gregg ◽  
Joshua Deignan ◽  
...  
Keyword(s):  
Lactic Acidosis ◽  
Neonatal Death ◽  
Clinical Manifestations ◽  
Compound Heterozygous ◽  
Sequencing Analysis ◽  
Suspected Sepsis ◽  
Whole Exome ◽  
The Family ◽  
Biochemical Analyses ◽  
Male Neonate

A term male neonate developed severe intractable lactic acidosis on day of life 1 and died the same day at our institution. The family previously lost another term, female newborn on day of life 1 from suspected sepsis at an outside hospital. After performing an autopsy on the neonate who died at our institution, extensive and lengthy neonatal and parental genetic testing, as well as biochemical analyses, and whole exome sequencing analysis identified compound heterozygous mutations in the lipoyltransferase 1 (LIPT1)gene responsible for the lipoylation of the 2-keto dehydrogenase complexes in the proband. These mutations were also identified in the deceased sibling. The clinical manifestations of these two siblings are consistent with those recently described in two unrelated families with lactic acidosis due toLIPT1mutations, an underrecognized and underreported cause of neonatal death.Conclusions. Our observations contribute to the delineation of a new autosomal recessive metabolic disorder, leading to neonatal death. Our case report also highlights the importance of an interdisciplinary team in solving challenging cases.

scholarly journals Whole exome sequencing identifies compound heterozygous variants of CR2 gene in monozygotic twin patients with common variable immunodeficiency

2020 ◽  
Vol 8 ◽  
pp. 205031212092265
Author(s):  
Adiratna Mat Ripen ◽  
Hamidah Ghani ◽  
Chai Teng Chear ◽  
Mei Yee Chiow ◽  
Sharifah Nurul Husna Syed Yahya ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Complex Disease ◽  
Monozygotic Twins ◽  
Compound Heterozygous ◽  
Sequencing Analysis ◽  
Missense Mutations ◽  
Upper Respiratory Tract ◽  
Whole Exome ◽  
Tract Infections

Objectives: A pair of female Malay monozygotic twins who presented with recurrent upper respiratory tract infections, hepatosplenomegaly, bronchiectasis and bicytopenia were recruited in this study. Both patients were suspected with primary immunodeficiency diseases. However, the definite diagnosis was not clear due to complex disease phenotypes. The objective of this study was to identify the causative gene mutation in these patients. Methods: Lymphocyte subset enumeration test and whole exome sequencing were performed. Results: We identified a compound heterozygous CR2 mutation (c.1916G>A and c.2012G>A) in both patients. These variants were then confirmed using Sanger sequencing. Conclusion: Whole exome sequencing analysis of the monozygotic twins revealed compound heterozygous missense mutations in CR2.

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).

scholarly journals Understanding What You Have Found: A Family With a Mutation in the LAMA1 Gene With Literature Review

2020 ◽  
Vol 13 ◽  
pp. 117954762094866
Author(s):  
Muhsin Elmas ◽  
Basak Gogus ◽  
Mustafa Solak
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Imaging Finding ◽  
Large Data ◽  
Compound Heterozygous ◽  
Homozygous Mutation ◽  
Sequencing Analysis ◽  
Recessive Inheritance ◽  
Data Generation ◽  
Whole Exome

Introduction: Cerebellar dysplasia with cysts (CDC) is an imaging finding which is typically seen with in individuals with dystroglycanopathy. One of the diseases causing this condition is “Poretti-Boltshauser Syndrome; PTBHS” (OMIM #615960). Homozygous or compound heterozygous mutations in the LAMA1 gene cause this disease. Case presentation: 7 years old twin siblings consulted to the medical genetics department because of walking problems and cerebellar examination findings. Management and Outcome: Clinical and radiological findings of the patient suggested a syndrome with recessive inheritance. Whole exome sequencing (WES) test was performed for definitive diagnosis. As a result of the patient’s WES analysis, a homozygous mutation was detected in the LAMA1 gene. Discussion: When determining the inheritance pattern of genetic diseases, if parents have consanquinity, this situation leads us to recessive inheritance diseases. Even if we are not consanquinity, but they say the same village, it is necessary to pay attention to the diseases of the recessive group. Whole exome sequencing analysis results in large amount of data generation. A good clinical evaluation is required to detect the mutation as a result of large data. To understand what we have found, we need to know what we are looking for.

scholarly journals A Twins Case of Lissencephaly With GPR56 Compound Heterozygous Mutations and Literatures Review

2021 ◽  
Author(s):  
Wenxin Lin ◽  
Yingying Chai ◽  
Xia Zhang ◽  
Tingting Huang ◽  
Guo Zheng ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Clinical Manifestations ◽  
Compound Heterozygous ◽  
The Novel ◽  
Chain Reaction ◽  
Causative Gene ◽  
Whole Exome ◽  
Malformation Of Cortical Development ◽  
Hypothalamic Pituitary Axis ◽  
Polymerase Chain

Abstract Background: Lissencephaly (LIS) is a malformation of cortical development characterized by developmental delay and seizure in combination with wide gyrus, superficial sulcus, and thickened cortex. Up to date, 20 genes have been implicated in LIS. However, GRP56-related LIS has never been reported, which was considered one causative gene for bilateral frontoparietal polymicrogyria(BFPP). Methods: Genetic testing of the proband was performed by whole exome sequencing and mainly analyzed 662 genes related to brain hypoplasia, white matter abnormalities, and hypothalamic-pituitary axis abnormalities such us AAAS, AARS2, ABAT, ABCC8, etc.. And the candidate mutations were further confirmed by polymerase chain reaction (PCR) and Sanger sequencing. Though we did genetic testing on the twin sisters and their parents, we could only obtain the clinical data of the older sister.Results: We reported a case of LIS twins, form a nonconsanguineous family, both carried the novel compound heterozygous GPR56 mutations, p.F76fs and p.H607fs.The older sister manifested lissencephaly, seizures, and flathead deformity and the younger sister had lissencephaly. We summarized their clinical characteristics and reviewed all the literatures of LIS and GPR56 to further clarify the correlation between genotype and phenotype.Conclusion: The LIS twins with GPR56 mutations were the first reported. By reviewing the clinical manifestations of LIS and GPR56 mutations, we validated the association between them, and broaden the clinical manifestations of GPR56 related phenotypes, indicating the importance of GPR56 screening in LIS patients.

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.

P0065DOUBLE MUTATION INHERITANCE IN PATIENTS WITH FOCAL SEGMENTAL GLOMERULOSCLEROSIS AND ALPORT SUNDROME

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Jingyuan Xie
Keyword(s):  
Genetic Analysis ◽  
Focal Segmental Glomerulosclerosis ◽  
Clinical Symptoms ◽  
Compound Heterozygous ◽  
Incomplete Penetrance ◽  
Digenic Inheritance ◽  
Segmental Glomerulosclerosis ◽  
Whole Exome ◽  
The Family ◽  
Genetic Pools

Abstract Background and Aims Focal segmental glomerulosclerosis (FSGS) and Alport syndrome (AS) are the leading causes of ESRD globally. FSGS and AS are clinically heterogeneous nephropathies and mainly genetic causes are the mutations in genes expressed in podocytes and glomerular basement membrane (GBM) respectively. A simple Mendelian model fail to explain the genetic control of both nephropathies completely because of the heterogeneous nature and presence of incomplete penetrance. Therefore, here we investigated the possible digenic control of FSGS and AS. Method To detect the double mutational (mono- or di-genic) cause of FSGS and AS, we conducted whole exome sequencing (WES) and panel sequencing in 67 kidney patients during the period of four years (2015 to June 2019). Inclusion criteria was the proband's clinical symptoms confirming the FSGS or AS based on clinical symptoms and renal biopsy. Clinical and genetic analyses were implemented to correlate the phenotypes with genotypes. Results Genetic analysis discovered that 35 out of 67 (52.23%) had genetic cause of selected nephropathies and 24 out of 35 (68.57%) had mutations in COL4A (3,4 & 5) genes and 11 (31.42%) in other genes. Interestingly, we found 7 out of 35 patients (20%) with double mutations (mono- or di-genic) in COL4A3/COL4A4 genes. After the mentioned period, during routine genetic screening, we also found another patient having double mutations in COL4A3 gene. Subsequently, Sanger sequencing confirmed that the identified mutations were co-segregating with the disease(s) in an incomplete penetrance fashion within the family. Lastly, we found 16 mutations in 8 patients having either monogenic or digeneic double mutations in COL4A3 and/or COL4A4 genes. In sum, we found 12 (75%) mutations in COL4A3 and 4 in COL4A4 (25%), and5 probands (62.5%) had compound heterozygous mutations in COL4A3, 1 proband (12.5%) had in COL4A4 and 2 probands (25%) had digenic (COL4A3/COL4A4) mutations. Last of all, among all the mutations, 10 were novel and 6 have been described previously. Conclusion This genetic analysis provides the first evidence for digenic inheritance of FSGS. The nephrologists and clinical geneticists should keep this possibility in mind for the accuracy in diagnosis, disease management and genetic counseling in future. Additionally, we are also adding 10 novel mutations in COL4A3 and COL4A4 genetic pools.

scholarly journals Rapid Trio Exome Sequencing for Autosomal Recessive Renal Tubular Dysgenesis in Recurrent Oligohydramnios

2021 ◽  
Vol 12 ◽  
Author(s):  
Shin-Yu Lin ◽  
Gwo-Tsann Chuang ◽  
Chien-Hui Hung ◽  
Wei-Chou Lin ◽  
Yung-Ming Jeng ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Neonatal Death ◽  
Autosomal Recessive ◽  
Compound Heterozygous Mutation ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Early Neonatal Death ◽  
Renal Tubular Dysgenesis ◽  
Whole Exome ◽  
Renal Tubular

Oligohydramnios is not a rare prenatal finding. However, recurrent oligohydramnios is uncommon, and genetic etiology should be taken into consideration. We present two families with recurrent fetal oligohydramnios that did not respond to amnioinfusion. Rapid trio-whole-exome sequencing (WES) revealed mutations in the AGT gene in both families within 1 week. The first family had a compound heterozygous mutation with c.856 + 1G > T and c.857-619_1269 + 243delinsTTGCCTTGC changes. The second family had homozygous c.857-619_1269 + 243delinsTTGCCTTGC mutations. AGT gene mutation may lead to autosomal recessive renal tubular dysgenesis, a rare and lethal disorder that can result in early neonatal death. Both the alleles identified are known alleles associated with pathogenicity. Our findings suggest that trio-WES analysis may help rapidly identify causative etiologies that can inform prompt counseling and decision-making prenatally.

scholarly journals Whole-exome sequencing as a powerful tool for identifying genetic causes in a patient with POLG-related disorders and phenylketonuria

2019 ◽  
Vol 47 (3) ◽  
pp. 1387-1394 ◽  
Author(s):  
Lin Li ◽  
Jin-Qi Zhao ◽  
Chengrong Wang ◽  
Nan Yang ◽  
Li-Fei Gong ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Mental Retardation ◽  
Liver Disease ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Compound Heterozygous ◽  
Sequencing Analysis ◽  
Genetic Causes ◽  
Whole Exome ◽  
Compound Heterozygous Mutations

Objective This study’s aim was to identify the genetic causes in a patient with phenylketonuria and hearing loss, liver disease, developmental and mental retardation, hypotonia, and external ophthalmoplegia. Methods Whole-exome sequencing and Sanger sequencing analysis were used to determine the genetic causes of manifestations in a young boy with hearing loss, liver disease, develop-mental and mental retardation, hypotonia, and external ophthalmoplegia. Results We found that the child harbored polymerase gamma ( POLG) compound heterozygous mutations, c.2617G>A (p.E873K) and c.3550G>A (p.D1184N), and phenylalanine hydroxylase ( PAH) compound heterozygous mutations, c.721C>T (p.R241C) and c.728G>A (p.R243Q). Among them, the POLG p.E873K mutation is a novel mutation and is not present in the Exome Aggregation Consortium database, Genome Aggregation database, and 1000 Genomes database. The two heterozygous mutations were each inherited from both of the child’s parents. This finding suggested that the phenotype and the genotype were segregated. Conclusion Using whole-exome sequencing, we not only identified PAH mutations causing phenylketonuria, but also identified the genetic cause of the mitochondrial disease and found a novel POLG mutation. Our findings could be useful in helping future parents obtain healthy embryos through assisted reproductive technology.

scholarly journals Identification of a Mutation in the Novel Compound Heterozygous CFTR in a Chinese Family with Cystic Fibrosis

2020 ◽  
Vol 2020 ◽  
pp. 1-5
Author(s):  
Hongxia Shao ◽  
Jingna Hua ◽  
Qi Wu ◽  
Xiaoge Li ◽  
Ming Zhang ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Clinical Manifestations ◽  
Chinese Patients ◽  
Clinical Samples ◽  
Compound Heterozygous Mutation ◽  
Chinese Family ◽  
Compound Heterozygous ◽  
The Novel ◽  
Airway Infections ◽  
The Family

Cystic fibrosis (CF) is one of the most common autosomal recessive disorders among Caucasians of Northern European descent but is uncommon in the Chinese population. Objectives. To elucidate the mutation in the novel compound heterozygous CFTR causing CF in Chinese family. Materials and Methods. Clinical samples were obtained from a Chinese family, the brother and sister with recurrent airway infections, hypoxemia and obstructive ventilatory impairment, sinusitis, clubbed fingers, salty sweat, and nasal polyposis. We performed whole-exome sequencing on the family and validated all potential variants by Sanger sequencing. Results. Next-generation sequencing showed a novel compound heterozygous CFTR mutation (c.400 A > G p.Arg134Gly and c.3484 C > T p.Arg1162∗) which resulted in CF in the family. Conclusions. As this mutation is consistent with the observed clinical manifestations of CF and no other mutations were detected after scanning the gene sequence, we suggest that their CF phenotypes are caused by the compound heterozygous mutation, c.400 A > G p.Arg134Gly and c.3484 C > T p.Arg1162∗. As c.400 A > G is not currently listed in the Cystic Fibrosis Mutation Database, this information, regarding the CF-causing mutations in two Chinese patients, is of interest.

scholarly journals Novel Compound Heterozygous BBS2 and Homozygous MKKS Variants Detected in Chinese Families with Bardet–Biedl Syndrome

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Li Huang ◽  
Limei Sun ◽  
Zhirong Wang ◽  
Songshan Li ◽  
Chonglin Chen ◽  
...  
Keyword(s):  
Clinical Manifestations ◽  
High Body Mass Index ◽  
Sex Characteristics ◽  
Compound Heterozygous ◽  
Chinese Families ◽  
Bardet Biedl Syndrome ◽  
Secondary Sex Characteristics ◽  
Whole Exome ◽  
Systemic Manifestations ◽  
Compound Heterozygous Variants

Background. Bardet–Biedl syndrome (BBS) is a rare multisystem developmental disorder. In this study, we report the genetic causes and clinical manifestations in two Chinese families with BBS. Materials and Methods. Two families were recruited in this study. Family A was a four-generation family with four affected and 15 unaffected members participating in the study, and family B was a consanguineous family with one affected and three unaffected members participating. Whole exome sequencing was performed in the two families, followed by a multistep bioinformatics analysis. Sanger sequencing was used to verify the variants and to perform a segregation analysis. Comprehensive ocular and systemic examinations were also conducted. Results. Novel compound heterozygous variants c.235T > G (p.T79P) and c.534 + 1G > T were detected in the BBS2 gene in family A, and known homozygous variant c.748G > A (p.G250R) was detected in the MKKS gene in family B. Both families presented with retinitis pigmentosa; however, except for polydactyly, all other systemic manifestations were different. All of the affected family members in family A were overweight with a high body mass index (range from 26.5 to 41.9) and high blood pressure. Family A also presented with a delay in the onset of secondary sex characteristics and genital anomalies, while other systemic abnormalities were absent in family B. Conclusions. This study presents one family with two novel BBS2 variants, expanding the variant spectrum of BBS, and one family with a known homozygous MKKS variant. The different phenotypes seen between the families with BBS2 and MKKS variants will contribute to the literature and our overall understanding of BBS.

Sign in / Sign up

Export Citation Format

Share Document