Genomic medicine for undiagnosed diseases

Wise, Anastasia L.; Manolio, Teri A.; Mensah, George A.; Peterson, Josh F.; Roden, Dan M.; Tamburro, Cecelia P.; Williams, Marc S.; Green, Eric D.

doi:10.1016/s0140-6736(19)31274-7

Cited by 92 publications

(64 citation statements)

References 48 publications

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“…Chromosomal microarray is preferred as a first‐line test over routine karyotype because of its higher genomic resolution . Recent years have seen the growing implementation of exome sequencing (ES) technique into widespread clinical use, shortening the diagnostic odyssey for many families with rare monogenic disorders . Although it is currently more commonly utilized in affected pediatric and adult patients, the practice in prenatal setting is also gaining momentum.…”

Section: Introductionmentioning

confidence: 99%

Rapid prenatal diagnosis of skeletal dysplasia using medical trio exome sequencing: Benefit for prenatal counseling and pregnancy management

Han

Yang

et al. 2020

Prenatal Diagnosis

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Objective: The aim of this study is to explore the utility of rapid medical trio exome sequencing (ES) for prenatal diagnosis using the skeletal dysplasia as an exemplar.Method: Pregnant women who were referred for genetic testing because of ultrasound detection of fetal abnormalities suggestive of a skeletal dysplasia were identified prospectively. Fetal samples (amniocytes or cord blood), along with parental blood, were send for rapid copy number variations testing and medical trio ES in parallel.Results: Definitive molecular diagnosis was made in 24/27 (88.9%) cases. Chromosomal abnormality (partial trisomy 18) was detected in one case. Sequencing results had explained the prenatal phenotype enabling definitive diagnoses to be made in 23 cases. There were 16 de novo dominant pathogenic variants, four dominant pathogenic variants inherited maternally or paternally, two recessive conditions with pathogenic variants inherited from unaffected parents, and one X-linked condition. The turnaround time from receipt of samples in the laboratory to reporting sequencing results was within 2 weeks.Conclusion: Medical trio ES can yield very timely and high diagnostic rates in fetuses presenting with suspected skeletal dysplasia. These definite diagnoses aided parental counseling and decision making in most of cases.

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Section: Introductionmentioning

confidence: 99%

Rapid prenatal diagnosis of skeletal dysplasia using medical trio exome sequencing: Benefit for prenatal counseling and pregnancy management

Han

Yang

et al. 2020

Prenatal Diagnosis

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“…[11][12][13][14][15][16][17][18][19] Due to inter-related reasons, however, previous studies have been able to provide limited assessments. [20][21][22] First, most studies have not recorded sufficient breadth of data to consider, both separately and in combination, the impact of using information on conventional risk predictors, PRS, and a panel of clinical biochemistry markers (beyond total-and HDLcholesterol). Second, previous studies have tended to involve moderate statistical power, whereas a high degree of power is needed to make reliable comparisons using such molecular data.…”

Section: Introductionmentioning

confidence: 99%

Use of polygenic risk scores and other molecular markers to enhance cardiovascular risk prediction: prospective cohort study and modelling analysis

Sun

Pennells

Kaptoge

et al. 2019

Preprint

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“…Then, functional information from model organisms (Drosophila, Zebra Fish, Caenorhabditis elegans, etc. ), RNA sequencing (trascriptoma) and data about small molecule metabolites (metaboloma) can enhance diagnostic yield in undiagnosed conditions [35,39].…”

Section: Discussionmentioning

confidence: 99%

Improving diagnosis for rare diseases: the experience of the Italian undiagnosed Rare diseases network

et al. 2020

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Background For a number of persons with rare diseases (RDs) a definite diagnosis remains undiscovered with relevant physical, psychological and social consequences. Undiagnosed RDs (URDs) require other than specialised clinical centres, outstanding molecular investigations, common protocols and dedicated actions at national and international levels; thus, many “Undiagnosed RDs programs” have been gradually developed on the grounds of a well-structured multidisciplinary approach. Methods The Italian Undiagnosed Rare Diseases Network (IURDN) was established in 2016 to improve the level of diagnosis of persons with URD living in Italy. Six Italian Centres of Expertise represented the network. The National Centre for Rare Diseases at the Istituto Superiore di Sanità coordinates the whole project. The software PhenoTips was used to collect the information of the clinical cases. Results One hundred and ten cases were analysed between March 2016 and June 2019. The age of onset of the diseases ranged from prenatal age to 51 years. Conditions were predominantly sporadic; almost all patients had multiple organs involvements. A total of 13/71 family cases were characterized by WES; in some families more than one individual was affected, so leading to 20/71 individuals investigated. Disease causing variants were identified in two cases and were associated to previously undescribed phenotypes. In 5 cases, new candidate genes were identified, although confirmatory tests are pending. In three families, investigations were not completed due to the scarce compliance of members and molecular investigations were temporary suspended. Finally, three cases (one familial) remain still unsolved. Twelve undiagnosed clinical cases were then selected to be shared at International level through PhenomeCentral in accordance to the UDNI statement. Conclusions Our results showed a molecular diagnostic yield of 53,8%; this value is comparable to the diagnostic rates reported in other international studies. Cases collected were also pooled with those collected by UDNI International Network. This represents a unique example of global initiative aimed at sharing and validating knowledge and experience in this field. IURDN is a multidisciplinary and useful initiative linking National and International efforts aimed at making timely and appropriate diagnoses in RD patients who still do not have a confirmed diagnosis even after a long time.

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Genomic medicine for undiagnosed diseases

Cited by 92 publications

References 48 publications

Rapid prenatal diagnosis of skeletal dysplasia using medical trio exome sequencing: Benefit for prenatal counseling and pregnancy management

Rapid prenatal diagnosis of skeletal dysplasia using medical trio exome sequencing: Benefit for prenatal counseling and pregnancy management

Use of polygenic risk scores and other molecular markers to enhance cardiovascular risk prediction: prospective cohort study and modelling analysis

Improving diagnosis for rare diseases: the experience of the Italian undiagnosed Rare diseases network

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