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Comprehensive massive parallel DNA sequencing strategy for the genetic diagnosis of the neuro-cardio-facio-cutaneous syndromes.

ABSTRACT: Variants in 11 genes of the RAS/MAPK signaling pathway have been causally linked to the neuro-cardio-facio-cutaneous syndromes group (NCFCS). Recently, A2ML1 and RIT1 were also associated with these syndromes. Because of the genetic and clinical heterogeneity of NCFCS, it is challenging to define strategies for their molecular diagnosis. The aim of this study was to develop and validate a massive parallel sequencing (MPS)-based strategy for the molecular diagnosis of NCFCS. A multiplex PCR-based strategy for the enrichment of the 13 genes and a variant prioritization pipeline was established. Two sets of genomic DNA samples were studied using the Ion PGM System: (1) training set (n =15) to optimize the strategy and (2) validation set (n = 20) to validate and evaluate the power of the new methodology. Sanger sequencing was performed to confirm all variants and low covered regions. All variants identified by Sanger sequencing were detected with our MPS approach. The methodology resulted in an experimental approach with a specificity of 99.0% and a maximum analytical sensitivity of ? 98.2% with a confidence of 99%. Importantly, two patients (out of 20) harbored described disease-causing variants in genes that are not routinely tested (RIT1 and SHOC2). The addition of less frequently altered genes increased in ? 10% the diagnostic yield of the strategy currently used. The presented workflow provides a comprehensive genetic screening strategy for patients with NCFCS in a fast and cost-efficient manner. This approach demonstrates the potential of a combined MPS-Sanger sequencing-based strategy as an effective diagnostic tool for heterogeneous diseases.

SUBMITTER: Justino A

PROVIDER: S-EPMC4326724 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Comprehensive massive parallel DNA sequencing strategy for the genetic diagnosis of the neuro-cardio-facio-cutaneous syndromes.

Justino Ana A Dias Patrícia P João Pina Maria M Sousa Sónia S Cirnes Luís L Berta Sousa Ana A Carlos Machado José J Costa José Luis JL

European journal of human genetics : EJHG 20140604 3

Variants in 11 genes of the RAS/MAPK signaling pathway have been causally linked to the neuro-cardio-facio-cutaneous syndromes group (NCFCS). Recently, A2ML1 and RIT1 were also associated with these syndromes. Because of the genetic and clinical heterogeneity of NCFCS, it is challenging to define strategies for their molecular diagnosis. The aim of this study was to develop and validate a massive parallel sequencing (MPS)-based strategy for the molecular diagnosis of NCFCS. A multiplex PCR-based ...[more]

PMID: 24896146

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Project description:Backgroundcardio-facio-cutaneous syndrome is a rare genetic disorder affecting less than 900 people in the world. It is mainly characterized by craniofacial, dermatologic and cardiac defects, but also gastroenterological symptoms may be present, ranging from feeding difficulties to gastroesophageal reflux and constipation.In this report we describe a case of this syndrome characterized by severe feeding and growth difficulties, with a particular focus on the management of gastroenterological complications.Case presentationthe patient was a caucasian male affected by Cardio-Facio-Cutaneous syndrome who presented feeding difficulties already a few hours after birth. These symptoms worsened in the following months and lead to a complete growth arrest and malnutrition. He was first treated with a nasogastric tube placement. Subsequently, a laparoscopic Nissen fundoplication and a laparoscopic Stamm gastrostomy were performed. The child was fed with nocturnal enteral nutrition and diurnal oral and enteral nutrition. Eventually the patient resumed feeding validly and regained adequate growth.Conclusionthis paper aims to bring to light a complex rare syndrome that infrequently comes to the attention of the pediatricians and whose diagnosis is not always straightforward. We also highlight the possible complications under a gastroenterologic point of view. Our contribution can be helpful to the pediatrician in the first diagnostic suspect of this syndrome. In particular, it is worth highlighting that -in an infant with Noonan-like features- symptoms like suction or swallowing problems, vomiting and feeding difficulties should orient towards the diagnosis of a Cardio-facio-cutaneous syndrome. It is also important to stress that its related gastroenterological issues may lead to severe growth failure and therefore the role of the gastroenterologist is key to manage supplemental feeding and to establish whether a nasogastric or gastrostomic tube placement is necessary.

Dataset Information

Comprehensive massive parallel DNA sequencing strategy for the genetic diagnosis of the neuro-cardio-facio-cutaneous syndromes.

Publications

Comprehensive massive parallel DNA sequencing strategy for the genetic diagnosis of the neuro-cardio-facio-cutaneous syndromes.

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