Unravelling the genetic landscape of early-onset emphysema by whole exome sequencing

Abstract Background Children with very early onset inflammatory bowel diseases (VEO-IBD) often have a refractory and severe disease course. A significant number of described VEO-IBD-causing monogenic disorders can be attributed to defects in immune-related genes. The diagnosis of the underlying primary immunodeficiency (PID) often has critical implications for the treatment of patients with IBD-like phenotypes. Methods To identify the molecular etiology in 5 patients from 3 unrelated kindred with IBD-like symptoms, we conducted whole exome sequencing. Immune workup confirmed an underlying PID. Results Whole exome sequencing revealed 3 novel CARMIL2 loss-of-function mutations in our patients. Immunophenotyping of peripheral blood mononuclear cells showed reduction of regulatory and effector memory T cells and impaired B cell class switching. The T cell proliferation and activation assays confirmed defective responses to CD28 costimulation, consistent with CARMIL2 deficiency. Conclusion Our study highlights that human CARMIL2 deficiency can manifest with IBD-like symptoms. This example illustrates that early diagnosis of underlying PID is crucial for the treatment and prognosis of children with VEO-IBD.

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Whole exome sequencing identifies FBN1 mutations in two patients with early-onset type B aortic dissection

Molecular Medicine Reports ◽

10.3892/mmr.2017.7410 ◽

2017 ◽

Vol 16 (5) ◽

pp. 6620-6625

Author(s):

Qian Han ◽

Wenwen Zhang ◽

Changjian Liu ◽

Min Zhou ◽

Feng Ran ◽

...

Keyword(s):

Aortic Dissection ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Early Onset ◽

Type B ◽

Type B Aortic Dissection ◽

Onset Type ◽

Whole Exome

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Whole-exome sequencing identifies compound heterozygous LHX4 mutations in a fetus with early-onset growth restriction

European Journal of Obstetrics & Gynecology and Reproductive Biology ◽

10.1016/j.ejogrb.2017.02.025 ◽

2017 ◽

Vol 211 ◽

pp. 225-227

Author(s):

Yue-Cheng Lu ◽

Lv-Ying Huang ◽

Jin-Mei Yan ◽

Yi Zhang ◽

Dong-Zhi Li

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Early Onset ◽

Growth Restriction ◽

Compound Heterozygous ◽

Whole Exome

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P2-131: WHOLE-EXOME SEQUENCING OF HISPANIC EARLY-ONSET ALZHEIMER DISEASE FAMILIES IDENTIFIES RARE VARIANTS IN MULTIPLE ALZHEIMER'S-RELATED GENES

Alzheimer s & Dementia ◽

10.1016/j.jalz.2014.05.806 ◽

2014 ◽

Vol 10 ◽

pp. P518-P519

Author(s):

Margaret Pericak-Vance ◽

Christiane Reitz ◽

Brian W. Kunkle ◽

Badri N. Vardarajan ◽

Martin A. Kohli ◽

...

Keyword(s):

Alzheimer Disease ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Early Onset ◽

Rare Variants ◽

Whole Exome

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Whole-exome sequencing reveals an inherited R566X mutation of the epithelial sodium channel β-subunit in a case of early-onset phenotype of Liddle syndrome

Molecular Case Studies ◽

10.1101/mcs.a001255 ◽

2016 ◽

Vol 2 (6) ◽

pp. a001255 ◽

Cited By ~ 6

Author(s):

Linda M. Polfus ◽

Eric Boerwinkle ◽

Richard A. Gibbs ◽

Ginger Metcalf ◽

Donna Muzny ◽

...

Keyword(s):

Sodium Channel ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Early Onset ◽

Epithelial Sodium Channel ◽

Β Subunit ◽

Liddle Syndrome ◽

Whole Exome

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Variable penetrance of CDH1 mutation diffuse gastric cancer: A genomic analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.4082 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 4082-4082

Author(s):

David Paul Kelsen ◽

Kasmintan A. Schrader ◽

Raya Khanin ◽

Laura H. Tang ◽

Erin E. Salo-Mullen ◽

...

Keyword(s):

Gastric Cancer ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Early Onset ◽

Germ Line ◽

Diffuse Gastric Cancer ◽

Second Hit ◽

Whole Exome ◽

Prophylactic Gastrectomy ◽

Variable Penetrance

4082 Background: CDH1 encodes E-cadherin; mutations (CDH1mut) increase the risk of diffuse gastric (DGC) and lobular breast cancers. Life-time risk of DGC is estimated at 80%. Current recommendations are prophylactic gastrectomy (PG) in CDH1mut carriers after age 20. Foci of DGC are found in some PG; others have none at PG, and some CDH1mut without PG never develop cancer. Identifying risk modifying alleles or other genomic events which increase the risk of DGC may improve understanding of DGC and may provide a biomarker for when to perform PG. Methods: For a Gastric Cancer Registry, we collected family pedigrees, germline DNA and FFPE tumor from CDH1mut DGC patients (pts) and their families. From 24 families, with 52 CDH1mut individuals, we identified 4 families in which a young CDH1mut pt developed advanced DGC while their CDH1mut parent and siblings had no clinical evidence of DGC. Several relatives had undergone PG with no DGC found. We hypothesize that there are risk modifying alleles and/or a “second hit” that causes variable penetrance and early onset of DGC in the young CDH1mut pts. Whole genome sequencing was performed on germ line DNA (Complete Genomics, Inc. Mountain View, CA); and whole exome sequencing on tumor specimens (MSKCC). Results: To date, 4 DGC pts and 8 relatives from 4 families have been studied. All 4 affected pts were women (ages 17, 25, 27, 42); their unaffected CDH1mut parents were 41, 51, 54, and 70 years old. The families are of Kenyan, Scandinavian, Italian, Eastern European, and Scottish origin. CDH1 mutations for the pts and their families were confirmed on WGS, and were as follows: 1451C>A(pro484his);c. 1792C>T (arg598ter);c. 1893dupA in exon 12;c. 1565+1G>A (IVS10+1G>A). Analysis of germline DNA for modifying alleles is being performed (Ingenuity Systems, Redwood, Ca.); whole exome sequencing of tumor to identify a possible "second hit" is underway. These data will be presented. Conclusions: Since at least some older pts with proven CDH-1mut do not develop DGC while their children do, CGH-1mut alone may not be sufficient to cause early onset DGC. We hope to identify the additional genomic events associated with early onset advanced DGC. Supported in part by grants from the Gerstner and DeGregorio Foundations.

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Whole-Exome sequencing identifies novel LEPR mutations in individuals with severe early onset obesity

Obesity ◽

10.1002/oby.20492 ◽

2013 ◽

Vol 22 (2) ◽

pp. 576-584 ◽

Cited By ~ 31

Author(s):

Richard Gill ◽

Yee Him Cheung ◽

Yufeng Shen ◽

Patricia Lanzano ◽

Nazrat M. Mirza ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Early Onset ◽

Whole Exome

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A maternal GOT1 novel variant associated with early-onset severe preeclampsia identified by whole-exome sequencing

10.21203/rs.2.15512/v5 ◽

2020 ◽

Author(s):

Lin Zhang ◽

Zheng Cao ◽

Fan Feng ◽

Ya-Nan Xu ◽

LIN LI ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Early Onset ◽

Molecular Mechanisms ◽

Bioinformatics Analysis ◽

Perinatal Death ◽

Association Studies ◽

Genome Wide Association Studies ◽

Mutation Site ◽

Whole Exome

Abstract Background This study wants to know the genetic cause of preeclampsia (PE) which is a leading cause of maternal and perinatal death, but the underlying molecular mechanisms that cause PE remain poorly understood. Many single nucleotide polymorphisms have been identified by genome-wide association studies and were found to be associated with PE; however, few studies have used whole-exome sequencing (WES) to identify PE mutations. Methods Five patients with severe early-onset preeclampsia (EOPE) were recruited, and WES was performed on each patient. Sanger sequencing was used to confirm the potential causative genetic mutation. Results After a stringent bioinformatics analysis, a rare mutation in the GOT1 gene, c.44C>G:p.P15R, was found in one patient. Bioinformatics analysis showed that the mutation site is highly conserved across several species and was predicted to be a pathogenic mutation according to several online mutational function prediction software packages. Further structural biology homology modeling suggested that P15R would change the electric environment of enzymatic center, and might affect the binding affinity of substrate or product. Conclusion We demonstrated for the first time that the mutation in GOT1 may be associated with EOPE, the results of this study provide researchers and clinicians with a better understanding of the molecular mechanisms that underlie maternal severe EOPE.

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