What Does This Mutation Mean? The Tools and Pitfalls of Variant Interpretation in Lymphoid Malignancies.

Yann G1, Jonathan L2,3,4, Kaddour C5, Sandrine H6,7, Claire B8,9, Gilles S10,11,12, Pierre S13,14,15, Sarah H16,17,18.

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Abstract

High throughput sequencing (HTS) is increasingly important in determining cancer diagnoses, with subsequent prognostic and therapeutic implications. The biology of cancer is becoming increasingly deciphered and it is clear that therapy needs to be individually tailored. Whilst translational research plays an important role in lymphoid malignancies, few guidelines exist to guide biologists and routine laboratories through this constantly evolving field. In this article, we review the challenges of interpreting HTS in lymphoid malignancies and provide a toolkit to interpret single nucleotide variants obtained from HTS. We define the pre-analytical issues such as sequencing DNA obtained from formalin-fixed and paraffin-embedded tissue (FFPE), the acquisition of germline DNA, or the bioinformatic pitfalls, the analytical issues encountered and how to manage them. We describe the main constitutional and cancer databases, their characteristics and limitations, with an emphasis on variant interpretation in lymphoid malignancies. Finally, we discuss the challenges of predictions that one can make using in silico or in vitro modelling, pharmacogenomic screening, and the limits of those prediction tools. This description of the current status in genomic interpretation highlights the need for new large databases and international collaboration in the lymphoma field.

KEYWORDS:

lymphoid malignancies; next-generation sequencing; variant interpretation

PMID:: 29677173
DOI:: 10.3390/ijms19041251

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Prevalence and Spectrum of BRCA1/2 Germline Mutations in Women with Breast Cancer in China Based on Next-Generation Sequencing. - PubMed - NCBI

2018 Apr 23;24:2465-2475.

Prevalence and Spectrum of BRCA1/2 Germline Mutations in Women with Breast Cancer in China Based on Next-Generation Sequencing.

Liang Y1, Yang X1, Li H1, Zhu A2, Guo Z1, Li M1.

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Abstract

BACKGROUND BRCA1 and BRCA2 (BRCA1/2) play important roles in the development of breast cancer, but information regarding BRCA1/2 mutations in Chinese females remains limited. The aim of this study was to investigate the prevalence and spectrum of BRCA1/2 mutations in China. MATERIAL AND METHODS In total, 595 breast cancer patients in China were screened with an amplicon-based panel for the detection of BRCA1/2 mutations in coding regions using next-generation sequencing (NGS) with a Personal Genome Machine. Every pathogenic mutation detected was confirmed by Sanger sequencing. The disease-causing potential of variants of uncertain significance (VUS) was predicted using PolyPhen-2, SIFT, PhyloP, and Grantham. RESULTS The prevalence of BRCA1/2 mutations was 8.07% in the Chinese population. Forty-two pathogenic mutations were identified in 48 cases (17 BRCA1 cases and 31 BRCA2 cases), including 19 novel mutations. Nine VUS were predicted to be deleterious by PolyPhen-2 and SIFT and subsequently predicted by PhyloP and Grantham for the evolutionary conservation. CONCLUSIONS These results suggest that NGS is useful as a rapid, high-throughput, and cost-effective screening tool for the analysis of BRCA1/2 mutations. Based on this panel, we found that BRCA1/2 germline mutations in China exhibit distinct characteristics compared to those in Western populations.

PMID:: 29681614

Genetic testing for clinically suspected spinocerebellar ataxias: report from a tertiary referral centre in India. - PubMed - NCBI

2018 Mar;97(1):219-224.

Genetic testing for clinically suspected spinocerebellar ataxias: report from a tertiary referral centre in India.

Venkatesh SD1, Kandasamy M, Moily NS, Vaidyanathan R, Kota LN, Adhikarla S, Yadav R, Pal PK, Jain S, Purushottam M.

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Abstract

Spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative syndromes, characterized by a wide range of muscular weakness and motor deficits, caused due to cerebellar degeneration. The prevalence of the syndromes of SCA varies across the world and is known to be linked to the instability of trinucleotide repeats within the high-end normal alleles, along with susceptible haplotype. We estimated sizes of the CAG or GAA repeat expansions at the SCA1, SCA2, SCA3, SCA12 and frataxin loci among 864 referrals of subjects to genetic counselling and testing (GCAT) clinic, National Institute of Mental Health and Neurosciences, Bengaluru, India, with suspected SCA. The most frequent mutations detected were SCA1 (n = 100 (11.6%)) and SCA2 (n = 98 (11.3%)) followed by SCA3 (n = 40 (4.6%)), FRDA (n = 20 (2.3%)) and SCA12 (n = 8 (0.9%)).

PMID:: 29666341

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Prenatal Correction of X-Linked Hypohidrotic Ectodermal Dysplasia. - PubMed - NCBI

2018 Apr 26;378(17):1604-1610. doi: 10.1056/NEJMoa1714322.

Prenatal Correction of X-Linked Hypohidrotic Ectodermal Dysplasia.

Schneider H1, Faschingbauer F1, Schuepbach-Mallepell S1, Körber I1, Wohlfart S1, Dick A1, Wahlbuhl M1, Kowalczyk-Quintas C1, Vigolo M1, Kirby N1, Tannert C1, Rompel O1, Rascher W1, Beckmann MW1, Schneider P1.

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Abstract

Genetic deficiency of ectodysplasin A (EDA) causes X-linked hypohidrotic ectodermal dysplasia (XLHED), in which the development of sweat glands is irreversibly impaired, an condition that can lead to life-threatening hyperthermia. We observed normal development of mouse fetuses with Eda mutations after they had been exposed in utero to a recombinant protein that includes the receptor-binding domain of EDA. We administered this protein intraamniotically to two affected human twins at gestational weeks 26 and 31 and to a single affected human fetus at gestational week 26; the infants, born in week 33 (twins) and week 39 (singleton), were able to sweat normally, and XLHED-related illness had not developed by 14 to 22 months of age. (Funded by Edimer Pharmaceuticals and others.).

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In Utero Protein Therapy for an Inherited Developmental Disorder. [N Engl J Med. 2018]
Prostate Cancer Metastasis - Fueled by Fat? [N Engl J Med. 2018]

PMID:: 29694819
DOI:: 10.1056/NEJMoa1714322

Infinitesimal Odds: A Scientist Finds Her Child’s Rare Illness Stems From the Gene She Studies - The New York Times

Infinitesimal Odds: A Scientist Finds Her Child’s Rare Illness Stems From the Gene She Studies

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By PAM BELLUCKAPRIL 23, 2018

Gene therapy helps patients avoid blood transfusion, study says - CNN

Gene therapy helps patients avoid blood transfusion, study says

By Jacqueline Howard, CNN

Updated 1257 GMT (2057 HKT) April 19, 2018

Autistic children may inherit DNA mutations from their fathers | Science | AAAS

Autistic children may inherit DNA

mutations from their fathers

By Matt WarrenApr. 19, 2018 , 2:00 PM

There is no one gene that, when mutated, causes autism. But over the past decade, researchers have identified hundreds of gene variations that seem to affect brain development in ways that increase the risk of autism. However, these scientists mainly searched for variants in the DNA that directly encodes the building blocks of proteins. Now, a new study probing so-called noncoding DNA has found that alterations in regions that regulate gene activity may also contribute to autism. And surprisingly, these variations tended to be inherited from fathers who aren’t autistic.