Lessons Learned from Whole Exome Sequencing in Multiplex Families Affected by a Complex Genetic Disorder, Intracranial Aneurysm

BackgroundCongenital anomalies of the kidney and urinary tract (CAKUT) are the most prevalent cause of kidney disease in the first three decades of life. Previous gene panel studies showed monogenic causation in up to 12% of patients with CAKUT.MethodsWe applied whole-exome sequencing to analyze the genotypes of individuals from 232 families with CAKUT, evaluating for mutations in single genes known to cause human CAKUT and genes known to cause CAKUT in mice. In consanguineous or multiplex families, we additionally performed a search for novel monogenic causes of CAKUT.ResultsIn 29 families (13%), we detected a causative mutation in a known gene for isolated or syndromic CAKUT that sufficiently explained the patient’s CAKUT phenotype. In three families (1%), we detected a mutation in a gene reported to cause a phenocopy of CAKUT. In 15 of 155 families with isolated CAKUT, we detected deleterious mutations in syndromic CAKUT genes. Our additional search for novel monogenic causes of CAKUT in consanguineous and multiplex families revealed a potential single, novel monogenic CAKUT gene in 19 of 232 families (8%).ConclusionsWe identified monogenic mutations in a known human CAKUT gene or CAKUT phenocopy gene as the cause of disease in 14% of the CAKUT families in this study. Whole-exome sequencing provides an etiologic diagnosis in a high fraction of patients with CAKUT and will provide a new basis for the mechanistic understanding of CAKUT.

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Case report: targeted whole exome sequencing enables the first prenatal diagnosis of the lethal skeletal dysplasia Osteocraniostenosis

BMC Medical Genetics ◽

10.1186/s12881-019-0939-z ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Lara Pemberton ◽

Robert Barker ◽

Anna Cockell ◽

Vijaya Ramachandran ◽

Andrea Haworth ◽

...

Keyword(s):

Case Report ◽

Prenatal Diagnosis ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Skeletal Dysplasia ◽

Genetic Disorder ◽

Specific Gene ◽

Ultrasound Images ◽

Whole Exome ◽

Lethal Skeletal Dysplasia

Abstract Background Osteocraniostenosis (OCS) is a rare genetic disorder characterised by premature closure of cranial sutures, gracile bones and perinatal lethality. Previously, diagnosis has only been possible postnatally on clinical and radiological features. This study describes the first prenatal diagnosis of OCS. Case presentation In this case prenatal ultrasound images were suggestive of a serious but non-lethal skeletal dysplasia. Due to the uncertain prognosis the parents were offered Whole Exome Sequencing (WES), which identified a specific gene mutation in the FAMIIIa gene. This mutation had previously been detected in two cases and was lethal in both perinatally. This established the diagnosis, a clear prognosis and allowed informed parental choice regarding ongoing pregnancy management. Conclusions This case report supports the use of targeted WES prenatally to confirm the underlying cause and prognosis of sonographically suspected abnormalities.

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The Use of Linkage Data To Prioritize Results from Whole Exome Sequencing in Familial Intracranial Aneurysm (S53.001)

Neurology ◽

10.1212/wnl.78.1_meetingabstracts.s53.001 ◽

2012 ◽

Vol 78 (Meeting Abstracts 1) ◽

pp. S53.001-S53.001

Author(s):

J. Farlow ◽

H. Lin ◽

K. Hetrick ◽

H. Ling ◽

D. Lai ◽

...

Keyword(s):

Intracranial Aneurysm ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Linkage Data ◽

Whole Exome

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A novel nonsense variant in SUPT20H gene associated with Rheumatoid Arthritis identified by Whole Exome Sequencing of multiplex families

PLoS ONE ◽

10.1371/journal.pone.0213387 ◽

2019 ◽

Vol 14 (3) ◽

pp. e0213387 ◽

Cited By ~ 2

Author(s):

Maëva Veyssiere ◽

Javier Perea ◽

Laetitia Michou ◽

Anne Boland ◽

Christophe Caloustian ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Whole Exome ◽

Multiplex Families

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Novel Pathogenic Variant in the Cys110 Residue: A Genotype–Phenotype Report of a Patient with Norrie Disease

Journal of Pediatric Genetics ◽

10.1055/s-0039-1700535 ◽

2019 ◽

Vol 09 (02) ◽

pp. 142-144

Author(s):

Jaspreet Garcha ◽

Angita Jain ◽

Herjot Atwal ◽

Pavalan Sevlam ◽

Paldeep S. Atwal

Keyword(s):

Retinal Detachment ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Clinical Phenotype ◽

Hot Spot ◽

Genetic Disorder ◽

Male Infant ◽

Norrie Disease ◽

Pathogenic Variants ◽

Whole Exome

AbstractNorrie disease is an X-linked genetic disorder caused by pathogenic mutations in the NDP. Here, we describe the clinical phenotype and genotype in a 19-week-old male infant with bilateral retinal detachment. Whole exome sequencing using available commercial methods on the proband revealed a hemizygous substitution in exon 3 of NDP, which suggests the etiology behind retinal detachment. This report not only adds to the expanding mutational spectrum of NDP-related retinopathies but also highlights the recurrence of pathogenic variants in the Cys110 residue, adding additional evidence to this residue as a potential mutational hot spot.

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Novel LRPPRC Mutation in a Boy With Mild Leigh Syndrome, French–Canadian Type Outside of Québec

Child Neurology Open ◽

10.1177/2329048x17737638 ◽

2017 ◽

Vol 4 ◽

pp. 2329048X1773763 ◽

Cited By ~ 5

Author(s):

Velda Xinying Han ◽

Teresa S. Tan ◽

Furene S. Wang ◽

Stacey Kiat-Hong Tay

Keyword(s):

Cytochrome C ◽

Exome Sequencing ◽

Cytochrome C Oxidase ◽

Whole Exome Sequencing ◽

Genetic Disorder ◽

Leigh Syndrome ◽

Compound Heterozygous ◽

French Canadian ◽

Metabolic Crisis ◽

Whole Exome

Background: Leigh syndrome, French–Canadian type is unique to patients from a genetic isolate in the Saguenay–Lac-Saint-Jean region of Québec. It has also been recently described in 10 patients with LRPPRC mutation outside of Québec. It is an autosomal recessive genetic disorder with fatal metabolic crisis and severe neurological morbidity in infancy caused by LRPPRC mutation. Methods and Results: The authors report a boy with a novel LRPPRC compound heterozygous missense mutations c.3130C>T, c.3430C>T, and c.4078G>A found on whole-exome sequencing which correlated with isolated cytochrome c-oxidase deficiency found in skeletal muscle. Conclusion: LRPPRC mutation is a rare cause of cytochrome c-oxidase–deficient form of Leigh syndrome outside of Québec. Our patient broadens the spectrum of phenotypes of Leigh syndrome, French–Canadian type. LRPPRC mutation should be considered in children with early childhood neurodegenerative disorder, even in the absence of metabolic crisis. Early evaluation with whole-exome sequencing is useful for early diagnosis and for genetic counseling.

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O1-09-02: Whole Exome Sequencing of Late Onset Multiplex Families Identifies Rare Coding Variants in Known and Novel Alzheimer’s Disease Genes

Alzheimer s & Dementia ◽

10.1016/j.jalz.2016.06.342 ◽

2016 ◽

Vol 12 ◽

pp. P196-P197

Author(s):

Holly N. Cukier ◽

Brian W. Kunkle ◽

Sophie Rolati ◽

Patrice L. Whitehead ◽

Jeffery M. Vance ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Late Onset ◽

Disease Genes ◽

Whole Exome ◽

Multiplex Families ◽

Coding Variants

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Turkish cases of Mabry Syndrome with a novel homozygous mutation in PGAP2 gene

10.21203/rs.3.rs-772787/v1 ◽

2021 ◽

Author(s):

Ayşe Kartal ◽

Sandeep Jaiswar

Keyword(s):

Alkaline Phosphatase ◽

Mental Retardation ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Genetic Disorder ◽

Missense Variant ◽

Homozygous Mutation ◽

Elevated Alkaline Phosphatase ◽

Dysmorphic Features ◽

Whole Exome

Abstract Hyperphosphatasia with mental retardation syndrome is a genetic disorder. We report two siblings aged three years and fourteen years who were investigated for global development delays, seizures and dysmorphic features. A novel missense variant, c.1003G>A (p. Ala335 Thr chr11.3,846,572 NM_001256236.1), in PGAP2 gene was identified using whole-exome sequencing. We highlight the significance of elevated alkaline phosphatase in patients with certain dysmorphic features, can lead to the diagnosis of hyperphosphatasia with mental retardation syndrome using exome sequencing.

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Case Report: Whole-Exome Sequencing With MLPA Revealed Variants in Two Genes in a Patient With Combined Manifestations of Spinal Muscular Atrophy and Duchenne Muscular Dystrophy

Frontiers in Genetics ◽

10.3389/fgene.2021.605611 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yu Xia ◽

Yijie Feng ◽

Lu Xu ◽

Xiaoyang Chen ◽

Feng Gao ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Spinal Muscular Atrophy ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Muscular Atrophy ◽

Genetic Disorder ◽

Clinical Manifestations ◽

Chinese Family ◽

Whole Exome

Spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD) are two common kinds of neuromuscular disorders sharing various similarities in clinical manifestations. SMA is an autosomal recessive genetic disorder that results from biallelic mutations of the survival motor neuron 1 gene (SMN1; OMIM 600354) on the 5q13 chromosome. DMD is an X-linked disorder caused by defects in the DMD gene (OMIM 300377) on the X chromosome. Here, for the first time, we report a case from a Chinese family who present with clinical manifestations of both two diseases, including poor motor development and progressive muscle weakness. We identified a homozygous deletion in exons 7 and 8 of the SMN1 gene and a deletion in exon 50 of the DMD gene by whole-exome sequencing (WES) and multiplex ligation-dependent probe amplification (MLPA). This case expands our understanding of diagnosis for synchronous SMA and DMD and highlights the importance of various genetic testing methods, including WES, in differential diagnosis of neuromuscular diseases.

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A Rare Variant of ANK3 Is Associated With Intracranial Aneurysm

Frontiers in Neurology ◽

10.3389/fneur.2021.672570 ◽

2021 ◽

Vol 12 ◽

Author(s):

Junyu Liu ◽

Xin Liao ◽

Jilin Zhou ◽

Bingyang Li ◽

Lu Xu ◽

...

Keyword(s):

Blood Vessel ◽

Intracranial Aneurysm ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Vascular Endothelial Cells ◽

Association Studies ◽

Bioinformatic Analysis ◽

Cell Junctions ◽

Whole Exome ◽

Sporadic Cases

Intracranial aneurysm (IA) is a cerebrovascular disorder in which abnormal dilation of a blood vessel results from weakening of the blood vessel wall. The aneurysm may rupture, leading to subarachnoid hemorrhage with severe outcomes. This study was conducted to identify the genetic factors involved in the etiology of IA. Whole-exome sequencing was performed in three IA-aggregate families to identify candidate variants. Further association studies of candidate variants were performed among sporadic cases and controls. Bioinformatic analysis was used to predict the functions of candidate genes and variants. Twenty variants were identified after whole-exome sequencing, among which eight were selected for replicative association studies. ANK3 c.4403G>A (p.R1468H) was significantly associated with IA (odds ratio 4.77; 95% confidence interval 1.94–11.67; p-value = 0.00019). Amino acid R1468 in ANK3 was predicted to be located in the spectrin-binding domain of ankyrin-G and may regulate the migration of vascular endothelial cells and affect cell–cell junctions. Therefore, the variation p.R1468H may cause weakening of the artery walls, thereby accelerating the formation of IA. Thus, ANK3 is a candidate gene highly related to IA.

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