Whole Exome Screening of Newborns

Study Overview
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Brief Summary
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The aim of the study is to obtain the initial experience of the inclusive genetic screening of newborn. Two groups of newborns born in RCOGP will be enlisted to the study: newborns without developmental features having no variations according to an inherited diseases screening; newborns showing either phenotypic features or deviations according to MS screening. The residual volume of the cord blood of all newborns form both groups will be collected and subjected to the whole exome sequencing. The sequencing data will be analyzed in screening mode for the first group while for the second group analysis will be performed taking the respective phenotype into account. The study is planned to cover 7000 newborns in total.

Official Title
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Development of the Technology and Methodology for Generation of the Genetic Passport (Genetic Health Record) of Newborn and Application Thereof to Estimate the Mid and Low Penetrance Hereditary Disorders Frequencies in Russian Population and to Uncover Genetic Factors Determining Severe Monogenic Conditions

Conditions
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Infant, Newborn

Intervention / Treatment
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* Genetic: Screening
* Genetic: Family history record
* Other: Questionnaire survey
* Genetic: Diagnostic
* Genetic: Selective screening


Participation Criteria
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Eligibility Criteria
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Group 1 (newborns without features): Inclusion Criteria: Infants born in the RCOGP, showing no development features and with no inherited diseases revealed by common screening Informed consent signed by a newborn's representative Exclusion Criteria: Parents refuse to participate Parent(s) younger 18 years Parent(s) unable to make decisions The infant is older 30 d Blood cannot be collected from the infant Group 2 (newborns with phenotypic features) Inclusion Criteria: Infants showing either phenotypic features or deviations according to MS screening Informed consent signed by a newborn's representative Exclusion Criteria: Parents refuse to participate Parent(s) younger 18 years Parent(s) unable to make decisions Blood cannot be collected from the infant Detailed description of the phenotype is not available The infant's exome has been already sequenced
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| unaffected<br>newborns without developmental features having no variations according to an inherited diseases screening; | Genetic: Screening<br>* Whole exome sequencing will be done and all infants will receive a report which will include pathogenic or likely pathogenic variants identified in genes associated with childhood-onset diseases for which specific care or prevention protocols are available. Families signed additional informed consent will receive an advanced report including variants with no care or prevention available, mid or low risk variants, and variants with late onset or those suggesting relatives to undergo screening.<br>Genetic: Family history record<br>* Families enrolled to the study will receive a genetic consult during which a family history will be taken concerning the inherited conditions.<br>Other: Questionnaire survey<br>* Families invited to the study will be asked to undergo a questionnaire survey regarding the reasons to accept or refuse the study, the familiarity of the aims, methods and outcomes of the study as well as the satisfaction.<br>|
| affected<br>newborns showing either phenotypic features or deviations according to MS screening | Genetic: Screening<br>* Whole exome sequencing will be done and all infants will receive a report which will include pathogenic or likely pathogenic variants identified in genes associated with childhood-onset diseases for which specific care or prevention protocols are available. Families signed additional informed consent will receive an advanced report including variants with no care or prevention available, mid or low risk variants, and variants with late onset or those suggesting relatives to undergo screening.<br>Genetic: Family history record<br>* Families enrolled to the study will receive a genetic consult during which a family history will be taken concerning the inherited conditions.<br>Other: Questionnaire survey<br>* Families invited to the study will be asked to undergo a questionnaire survey regarding the reasons to accept or refuse the study, the familiarity of the aims, methods and outcomes of the study as well as the satisfaction.<br>Genetic: Diagnostic<br>* The results of whole exome sequencing will be analysed according to the infant's phenotype in addition the the general screening pipeline<br>|
| refused families<br>parents refused to enroll their newborns to the study | Other: Questionnaire survey<br>* Families invited to the study will be asked to undergo a questionnaire survey regarding the reasons to accept or refuse the study, the familiarity of the aims, methods and outcomes of the study as well as the satisfaction.<br>|
| unaffected born prematurely<br>newborns without specific developmental features having no variations according to an inherited diseases screening, born before term | Genetic: Screening<br>* Whole exome sequencing will be done and all infants will receive a report which will include pathogenic or likely pathogenic variants identified in genes associated with childhood-onset diseases for which specific care or prevention protocols are available. Families signed additional informed consent will receive an advanced report including variants with no care or prevention available, mid or low risk variants, and variants with late onset or those suggesting relatives to undergo screening.<br>Genetic: Family history record<br>* Families enrolled to the study will receive a genetic consult during which a family history will be taken concerning the inherited conditions.<br>Other: Questionnaire survey<br>* Families invited to the study will be asked to undergo a questionnaire survey regarding the reasons to accept or refuse the study, the familiarity of the aims, methods and outcomes of the study as well as the satisfaction.<br>Genetic: Selective screening<br>* The results of whole exome sequencing will be analysed according to the data of prenatal ultrasound examination, family history and other available alarming information in addition the the general screening pipeline<br>|
| unaffected wirh family history<br>newborns without developmental features having no variations according to an inherited diseases screening but with affected relative(s) | Genetic: Screening<br>* Whole exome sequencing will be done and all infants will receive a report which will include pathogenic or likely pathogenic variants identified in genes associated with childhood-onset diseases for which specific care or prevention protocols are available. Families signed additional informed consent will receive an advanced report including variants with no care or prevention available, mid or low risk variants, and variants with late onset or those suggesting relatives to undergo screening.<br>Genetic: Family history record<br>* Families enrolled to the study will receive a genetic consult during which a family history will be taken concerning the inherited conditions.<br>Other: Questionnaire survey<br>* Families invited to the study will be asked to undergo a questionnaire survey regarding the reasons to accept or refuse the study, the familiarity of the aims, methods and outcomes of the study as well as the satisfaction.<br>Genetic: Selective screening<br>* The results of whole exome sequencing will be analysed according to the data of prenatal ultrasound examination, family history and other available alarming information in addition the the general screening pipeline<br>|
| unaffected wirh prenatal phenotype<br>newborns without developmental features at birth and on, having no variations according to an inherited diseases screening which had been observed to show signs of developmental features during prenatal ultrasound examination | Genetic: Screening<br>* Whole exome sequencing will be done and all infants will receive a report which will include pathogenic or likely pathogenic variants identified in genes associated with childhood-onset diseases for which specific care or prevention protocols are available. Families signed additional informed consent will receive an advanced report including variants with no care or prevention available, mid or low risk variants, and variants with late onset or those suggesting relatives to undergo screening.<br>Genetic: Family history record<br>* Families enrolled to the study will receive a genetic consult during which a family history will be taken concerning the inherited conditions.<br>Other: Questionnaire survey<br>* Families invited to the study will be asked to undergo a questionnaire survey regarding the reasons to accept or refuse the study, the familiarity of the aims, methods and outcomes of the study as well as the satisfaction.<br>Genetic: Selective screening<br>* The results of whole exome sequencing will be analysed according to the data of prenatal ultrasound examination, family history and other available alarming information in addition the the general screening pipeline<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estimate the frequency of revealing patients carrying genotype associated with a monogenic disese. | The manifestation of pathogenic or likely pathogenic variants leading to a monogenic disease presenting during early age. A genotype is considered having risk of developping a monogenic disease in case pathogenic or probably pathogenic variants are detected corresponding to the inheritance model. | 3-5 months | 
| Phenotype-associated variants | Pathogenic, likely pathogenic variants or variants of uncertain significance corresponding to the observed clinical conditions | 2 weeks - 2 months | 
| Motivations for refuse to participate | Questionnaire answers provided by families refused to enroll | 1 day | 
| Acceptance of advanced screening | Questionnaire answers provided by families accepted screening for variants of low penetrance, no care available etc. | 1 day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oncological risk | Pathogenic or a likely pathogenic variant causing high risk of developping a cancer | 1 day | 
| Cardiological risk | Pathogenic or a likely pathogenic variant causing high risk of developping a cardiomyopathy or a sudden cardiac death | 1 day | 
| Recessive carriers | Inheritance of a pathogenic or a likely pathogenic variant causing to an autosomal recessive disease | 1 day | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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newborn, whole exome, genetic screening