Fast genetic diagnosis of lysosomal disorders by means of a novel NGS-based resequencing gene panel

Aim Congenital hypopituitarism has an incidence of 1:3500–10,000 births and is defined by the impaired production of pituitary hormones. Early diagnosis has an impact on management and genetic counselling. The clinical and genetic heterogeneity of hypopituitarism poses difficulties to select the order of genes to analyse. The objective of our study is to screen hypopituitarism genes (candidate and previously related genes) simultaneously using a target gene panel in patients with congenital hypopituitarism. Methods Screening of 117 subjects with congenital hypopituitarism for pathogenic variants in 26 genes associated with congenital hypopituitarism by massively parallel sequencing using a customized target gene panel. Results We found three novel pathogenic variants in OTX2 c.295C>T:p.Gln99*, GLI2 c.1681G>T:p.Glu561* and GHRHR c.820_821insC:p.Asp274Alafs*113, and the previously reported variants in GHRHR c.57+1G>A and PROP1 [c.301_302delAG];[c.109+1G>A]. Conclusions Our results indicate that a custom-designed panel is an efficient method to screen simultaneously variants of biological and clinical relevance for congenital GH deficiency. A genetic diagnosis was possible in 5 out of 117 (4%) patients of our cohort. We identified three novel pathogenic variants in GHRHR, OTX2 and GLI2 expanding the spectrum of variants associated with congenital hypopituitarism.

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OP81 – 2242: Genetic diagnosis in early infantile epileptic encephalopathy and severe neurodevelopmental delay using a gene panel: Our experience and results so far

European Journal of Paediatric Neurology ◽

10.1016/s1090-3798(15)30082-9 ◽

2015 ◽

Vol 19 ◽

pp. S25-S26

Author(s):

N. Trump ◽

A. McTague ◽

M. Kurian ◽

A. Papandreou ◽

T. Cullup ◽

...

Keyword(s):

Genetic Diagnosis ◽

Epileptic Encephalopathy ◽

Gene Panel ◽

Neurodevelopmental Delay

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A Specially Designed Multi-Gene Panel Facilitates Genetic Diagnosis in Children with Intrahepatic Cholestasis: Simultaneous Test of Known Large Insertions/Deletions

PLoS ONE ◽

10.1371/journal.pone.0164058 ◽

2016 ◽

Vol 11 (10) ◽

pp. e0164058 ◽

Cited By ~ 13

Author(s):

Neng-Li Wang ◽

Yu-Lan Lu ◽

Ping Zhang ◽

Mei-Hong Zhang ◽

Jing-Yu Gong ◽

...

Keyword(s):

Intrahepatic Cholestasis ◽

Genetic Diagnosis ◽

Gene Panel ◽

Simultaneous Test

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Leukodystrophies and Genetic Leukoencephalopathies in Children Specified by Exome Sequencing in an Expanded Gene Panel

Journal of Child Neurology ◽

10.1177/0883073820904294 ◽

2020 ◽

Vol 35 (7) ◽

pp. 433-441

Author(s):

Bindu Parayil Sankaran ◽

Madhu Nagappa ◽

Shwetha Chiplunkar ◽

Sonam Kothari ◽

Periyasamy Govindaraj ◽

...

Keyword(s):

Exome Sequencing ◽

Genetic Diagnosis ◽

Gene Panel ◽

Unknown Etiology ◽

Mri Findings ◽

Diagnostic Challenge ◽

Variants Of Unknown Significance ◽

Pathogenic Variants ◽

Genetic Features ◽

Biopsy Confirmation

The overlapping clinical and neuroimaging phenotypes of leukodystrophies pose a diagnostic challenge to both clinicians and researchers alike. Studies on the application of exome sequencing in the diagnosis of leukodystrophies are emerging. We used targeted gene panel sequencing of 6440 genes to investigate the genetic etiology in a cohort of 50 children with neuroimaging diagnosis of leukodystrophy/genetic leukoencephalopathy of unknown etiology. These 50 patients without a definite biochemical or genetic diagnosis were derived from a cohort of 88 patients seen during a 2.5-year period (2015 January-2017 June). Patients who had diagnosis by biochemical or biopsy confirmation (n = 17) and patients with incomplete data or lack of follow-up (n = 21) were excluded. Exome sequencing identified variants in 30 (60%) patients, which included pathogenic or likely pathogenic variants in 28 and variants of unknown significance in 2. Among the patients with pathogenic or likely pathogenic variants, classic leukodystrophies constituted 13 (26%) and genetic leukoencephalopathies 15 (30%). The clinical and magnetic resonance imaging (MRI) findings and genetic features of the identified disorders are discussed.

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Review for "Genetic diagnosis of infantile‐onset epilepsy in the clinic: Application of whole‐exome sequencing following epilepsy gene panel testing"

10.1111/cge.13903/v2/review1 ◽

2020 ◽

Author(s):

Andrea Accogli

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Genetic Diagnosis ◽

Gene Panel ◽

Panel Testing ◽

Whole Exome ◽

Gene Panel Testing ◽

Epilepsy Gene

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PP2.0 – 2107 A new approach to genetic diagnosis in early infantile epileptic encephalopathy and severe neurodevelopmental delay using a gene panel

European Journal of Paediatric Neurology ◽

10.1016/s1090-3798(13)70110-7 ◽

2013 ◽

Vol 17 ◽

pp. S33

Author(s):

A Mctague ◽

RH Scott ◽

H Moody ◽

E Meyer ◽

S Drury ◽

...

Keyword(s):

Genetic Diagnosis ◽

Epileptic Encephalopathy ◽

Gene Panel ◽

New Approach ◽

Neurodevelopmental Delay

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Clinical and genetic characteristics of sporadic adult-onset degenerative ataxia

Neurology ◽

10.1212/wnl.0000000000004311 ◽

2017 ◽

Vol 89 (10) ◽

pp. 1043-1049 ◽

Cited By ~ 19

Author(s):

Ilaria Giordano ◽

Florian Harmuth ◽

Heike Jacobi ◽

Brigitte Paap ◽

Stefan Vielhaber ◽

...

Keyword(s):

Disease Duration ◽

Clinical Phenotype ◽

Genetic Diagnosis ◽

Gene Panel ◽

Unknown Etiology ◽

Specific Gene ◽

Adult Onset ◽

High Coverage ◽

Genetic Characteristics ◽

Cerebellar Type

Objective:To define the clinical phenotype and natural history of sporadic adult-onset degenerative ataxia and to identify putative disease-causing mutations.Methods:The primary measure of disease severity was the Scale for the Assessment and Rating of Ataxia (SARA). DNA samples were screened for mutations using a high-coverage ataxia-specific gene panel in combination with next-generation sequencing.Results:The analysis was performed on 249 participants. Among them, 83 met diagnostic criteria of clinically probable multiple system atrophy cerebellar type (MSA-C) at baseline and another 12 during follow-up. Positive MSA-C criteria (4.94 ± 0.74, p < 0.0001) and disease duration (0.22 ± 0.06 per additional year, p = 0.0007) were associated with a higher SARA score. Forty-eight participants who did not fulfill MSA-C criteria and had a disease duration of >10 years were designated sporadic adult-onset ataxia of unknown etiology/non-MSA (SAOA/non-MSA). Compared with MSA-C, SAOA/non-MSA patients had lower SARA scores (13.6 ± 6.0 vs 16.0 ± 5.8, p = 0.0200) and a slower annual SARA increase (1.1 ± 2.3 vs 3.3 ± 3.2, p = 0.0013). In 11 of 194 tested participants (6%), a definitive or probable genetic diagnosis was made.Conclusions:Our study provides quantitative data on the clinical phenotype and progression of sporadic ataxia with adult onset. Screening for causative mutations with a gene panel approach yielded a genetic diagnosis in 6% of the cohort.ClinicalTrials.gov registration:NCT02701036.

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