De novo mutations in CBL causing early-onset paediatric moyamoya angiopathy

2017 ◽  
Vol 54 (8) ◽  
pp. 550-557 ◽  
Author(s):  
Stéphanie Guey ◽  
Lou Grangeon ◽  
Francis Brunelle ◽  
Françoise Bergametti ◽  
Jeanne Amiel ◽  
...  
Keyword(s):  
Early Onset ◽  
De Novo ◽  
De Novo Mutations ◽  
Moyamoya Angiopathy

scholarly journals Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Ute I Scholl ◽  
Gabriel Stölting ◽  
Carol Nelson-Williams ◽  
Alfred A Vichot ◽  
Murim Choi ◽  
...  
Keyword(s):  
Calcium Channel ◽  
Primary Aldosteronism ◽  
Early Onset ◽  
De Novo ◽  
Incomplete Penetrance ◽  
De Novo Mutations ◽  
Channel Inactivation ◽  
Aldosterone Production ◽  
Genome Level ◽  
Insight Into

Many Mendelian traits are likely unrecognized owing to absence of traditional segregation patterns in families due to causation by de novo mutations, incomplete penetrance, and/or variable expressivity. Genome-level sequencing can overcome these complications. Extreme childhood phenotypes are promising candidates for new Mendelian traits. One example is early onset hypertension, a rare form of a global cause of morbidity and mortality. We performed exome sequencing of 40 unrelated subjects with hypertension due to primary aldosteronism by age 10. Five subjects (12.5%) shared the identical, previously unidentified, heterozygous CACNA1HM1549V mutation. Two mutations were demonstrated to be de novo events, and all mutations occurred independently. CACNA1H encodes a voltage-gated calcium channel (CaV3.2) expressed in adrenal glomerulosa. CACNA1HM1549V showed drastically impaired channel inactivation and activation at more hyperpolarized potentials, producing increased intracellular Ca2+, the signal for aldosterone production. This mutation explains disease pathogenesis and provides new insight into mechanisms mediating aldosterone production and hypertension.

scholarly journals De Novo Mutations in EIF2B1 Affecting eIF2 Signaling Cause Neonatal/Early-Onset Diabetes and Transient Hepatic Dysfunction

Diabetes ◽  
2019 ◽  
Vol 69 (3) ◽  
pp. 477-483 ◽  
Author(s):  
Elisa De Franco ◽  
Richard Caswell ◽  
Matthew B. Johnson ◽  
Matthew N. Wakeling ◽  
Amnon Zung ◽  
...  
Keyword(s):  
Early Onset ◽  
Hepatic Dysfunction ◽  
De Novo ◽  
De Novo Mutations ◽  
Onset Diabetes

De novo mutations in ATP1A2 and CACNA1A are frequent in early-onset sporadic hemiplegic migraine

Neurology ◽  
2010 ◽  
Vol 75 (11) ◽  
pp. 967-972 ◽  
Author(s):  
F. Riant ◽  
A. Ducros ◽  
C. Ploton ◽  
C. Barbance ◽  
C. Depienne ◽  
...  
Keyword(s):  
Early Onset ◽  
De Novo ◽  
De Novo Mutations ◽  
Hemiplegic Migraine

scholarly journals De Novo Mutations (GAG Deletion) in the DYT1 Gene in Two Non-Jewish Patients with Early-onset Dystonia

1998 ◽  
Vol 7 (7) ◽  
pp. 1133-1136 ◽  
Author(s):  
C. Klein ◽  
M. F. Brin ◽  
D. de Leon ◽  
S. A. Limborska ◽  
I. A. Ivanova-Smolenskaya ◽  
...  
Keyword(s):  
Early Onset ◽  
De Novo ◽  
De Novo Mutations ◽  
Dyt1 Gene

A de novo deletional germline mutation in the MLH1 gene resulting in early onset colorectal cancer in a woman with a negative family history: A case report

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 21067-21067
Author(s):  
D. Zakalik ◽  
N. S. Goldstein ◽  
W. L. Ducaine
Keyword(s):  
Colorectal Cancer ◽  
Family History ◽  
Early Onset ◽  
De Novo ◽  
Germline Mutations ◽  
De Novo Mutations ◽  
Mlh1 Gene ◽  
Negative Family History ◽  
Mmr Genes ◽  
Early Onset Colorectal Cancer

21067 Background: Hereditary non-polyposis colorectal cancer (HNPCC) is a genetic disorder that results in an increased risk of early onset colorectal cancer (CRC). HNPCC is caused by germline mutations in DNA mismatch repair (MMR) genes, including MLH1 and MSH2, and is transmitted in an autosomal dominant manner. De novo germline mutations in MMR genes are exceedingly rare. We now describe a case of a de novo germline mutation in MLH1 associated with early onset CRC in a young woman with a negative family history. Methods: We present a case of a 31-year-old Caucasian female who presented with abdominal pain. Colonoscopy revealed a moderately differentiated adenocarcinoma with focal mucin production involving the sigmoid colon, with a final staging of T4N0M0. Genetic testing was offered because of her young age at diagnosis, having fulfilled the Bethesda guidelines. Microsatellite instability (MSI) testing using a panel of six microsatellite loci was performed on the tumor sample from the affected patient. Immunohistochemistry (IHC) testing for MLH1 and MSH2 was performed. Following counseling and with informed consent, DNA was isolated and sequenced using bi-directional PCR of the MLH1 gene. All exons of MLH1 and MSH2 were analyzed by standard Southern blot methods. Paternity was established using eight genetic loci. Results: The patient's tumor revealed high MSI and complete absence of MLH1 immunoreactivity. MSH2 IHC staining was normal. A large deletional mutation involving exons 5–12 of MLH1 was identified by Southern blot analysis. The patient's parents and siblings were tested and found to have wild type MLH1. Paternity was confirmed with greater than 99.9% certainty. Conclusions: De novo mutations in MMR genes are a rare cause of HNPCC. We report the first case of a large de novo deletion in the MLH1 gene accounting for early onset CRC. Such de novo mutations, albeit rare, must be considered in patients who present with early onset CRC and a negative family history. These results support the use of the Bethesda guidelines to identify individuals who may carry mutations in the MMR genes. No significant financial relationships to disclose.

De Novo Mutations inSLC35A2Encoding a UDP-Galactose Transporter Cause Early-Onset Epileptic Encephalopathy

2013 ◽  
Vol 34 (12) ◽  
pp. 1708-1714 ◽  
Author(s):  
Hirofumi Kodera ◽  
Kazuyuki Nakamura ◽  
Hitoshi Osaka ◽  
Yoshihiro Maegaki ◽  
Kazuhiro Haginoya ◽  
...  
Keyword(s):  
Early Onset ◽  
De Novo ◽  
Epileptic Encephalopathy ◽  
De Novo Mutations

scholarly journals De Novo Mutations in YWHAG Cause Early-Onset Epilepsy

2017 ◽  
Vol 101 (2) ◽  
pp. 300-310 ◽  
Author(s):  
Ilaria Guella ◽  
Marna B. McKenzie ◽  
Daniel M. Evans ◽  
Sarah E. Buerki ◽  
Eric B. Toyota ◽  
...  
Keyword(s):  
Early Onset ◽  
De Novo ◽  
De Novo Mutations

De novo mutations in FLNC leading to early-onset restrictive cardiomyopathy and congenital myopathy

2018 ◽  
Vol 39 (9) ◽  
pp. 1161-1172 ◽  
Author(s):  
Artem Kiselev ◽  
Raquel Vaz ◽  
Anastasia Knyazeva ◽  
Aleksandr Khudiakov ◽  
Svetlana Tarnovskaya ◽  
...  
Keyword(s):  
Early Onset ◽  
De Novo ◽  
Restrictive Cardiomyopathy ◽  
Congenital Myopathy ◽  
De Novo Mutations

Novel de novo BRCA1 mutation in a woman with early onset breast cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e22143-e22143
Author(s):  
E. Tang ◽  
A. Kwong ◽  
C. Wong ◽  
F. Law ◽  
C. Wong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Family History ◽  
Early Onset ◽  
De Novo ◽  
Family Members ◽  
Gene Sequencing ◽  
Large Deletion ◽  
Early Onset Breast Cancer ◽  
De Novo Mutations ◽  
History Of

e22143 Background: Germline mutations in BRCA1/2 account for a significant portion of hereditary breast/ovarian cancer. Mutation carriers usually have a family history of breast/ovarian cancer or early onset disease. Rarely, germline mutations are found only in the probands but not in any family members. Such de novo mutations have been reported in diseases such as hemophilia A, thalassaemia and familial adenomatous polyposis. De novo mutations in the BRCA1 or BRCA2 genes are rare and the few reported have been in BRCA2. Here, we describe de novo as well as novel mutation of the BRCA1 gene in a breast cancer patient. Methods: Blood DNA samples from a 30 year old Chinese woman with breast cancer and no family history of cancer was tested for a BRCA1/2 mutation by full gene sequencing and Multiple Ligation-dependent Probe Amplification (MLPA). Family members were analyzed for the same mutation. Paternity was determined by a set of highly polymorphic short tandem repeat (STR) markers. Results: Full gene sequencing found no deleterious mutation. MLPA revealed a large deletion of exons 1 to 12 of BRCA1 in the proband. MLPA performed on 5 family members: proband's mother and father (who were 1st degree relative- cousins), stepmother (mother's biological sister), 2 sisters (1, same parents; 1, same father and stepmother) found no similar deletion. By using a set of highly polymorphic STR markers, the proband's father and mother were confirmed to be her biological parents. Conclusions: We report a novel de novo BRCA1 deletion mutation encompassing exons 1 - 12 in a Chinese breast cancer patient of early onset with no family history. Identification of this large deletion confirms the importance of pursuing rearrangement testing if full gene sequencing fails to detect a point mutation or short insertion deletion. The mutation found in this study is de novo. This may simply be a random mutation event which occurred in the parents' germ cells during their lifetime which passed onto one of their offspring or maybe a result of gene inversion or splicing deficiency. The relations of such mutations with consanguineous marriage cannot be ruled out. Mutation screening is important in early onset breast cancer patients even if there is no family history. No significant financial relationships to disclose.

scholarly journals Coding mutations inNUS1contribute to Parkinson’s disease

2018 ◽  
Vol 115 (45) ◽  
pp. 11567-11572 ◽  
Author(s):  
Ji-feng Guo ◽  
Lu Zhang ◽  
Kai Li ◽  
Jun-pu Mei ◽  
Jin Xue ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Early Onset ◽  
De Novo ◽  
Dopamine Level ◽  
De Novo Mutations ◽  
Functional Studies ◽  
Whole Exome ◽  
Independent Case ◽  
The Impact

Whole-exome sequencing has been successful in identifying genetic factors contributing to familial or sporadic Parkinson’s disease (PD). However, this approach has not been applied to explore the impact of de novo mutations on PD pathogenesis. Here, we sequenced the exomes of 39 early onset patients, their parents, and 20 unaffected siblings to investigate the effects of de novo mutations on PD. We identified 12 genes with de novo mutations (MAD1L1,NUP98,PPP2CB,PKMYT1,TRIM24,CEP131,CTTNBP2,NUS1,SMPD3,MGRN1,IFI35, andRUSC2), which could be functionally relevant to PD pathogenesis. Further analyses of two independent case-control cohorts (1,852 patients and 1,565 controls in one cohort and 3,237 patients and 2,858 controls in the other) revealed thatNUS1harbors significantly more rare nonsynonymous variants (P= 1.01E-5, odds ratio = 11.3) in PD patients than in controls. Functional studies inDrosophilademonstrated that the loss ofNUS1could reduce the climbing ability, dopamine level, and number of dopaminergic neurons in 30-day-old flies and could induce apoptosis in fly brain. Together, our data suggest that de novo mutations could contribute to early onset PD pathogenesis and identifyNUS1as a candidate gene for PD.

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