Role of the clinical genetic databases in a better performance of genetic counseling

دکتر معصومه فالح

دانشگاه علوم پزشکی و خدمات بهداشتی درمانی ایران پژوهشکده سالمت حواس پنجگانه مرکز تحقیقات گوش و حلق و بینی و سر و گردن Purpose of genetic counseling

Provide the family with complete and accurate information about genetic disorders.

 Promoting informed decisions

 Clarifying the family's options available treatment and prognosis

 Decreasing the incidence of genetic disorders

 Reducing the impact of the disorders Big data challenge

Clinical genetic testing has exponentially expanded

An overwhelming amount of patient variants

With high variability in pathogenicity and heterogeneous phenotypes. How do I learn about a genetic conditions?

Clinical Features

Modes of Inheritance Phenotypes

Practice Genes Guideline

MedGen

MedGen is NCBI’s portal to information about human disorders and other phenotypes having a genetic component Clinvar List of Professional Guidelines Gene Genetic Testing Registry (GTR®)

GeneReviews® OMIM®® ("aortic dissection"[Clinical Features]) AND "arachnodactyly"[Clinical Features] Table of contents •Disease characteristics •Additional descriptions •Clinical features Modes of inheritance: Autosomal dominant inheritance •Term Hierarchy Gene (location): FBN1 (15q21.1) OMIM®: 154700 •Professional guidelines Orphanet: ORPHA284963 •Suggested Reading •Recent clinical studies •Recent systematic reviews Marfan syndrome(MFS) Abnormality of limbs Arachnodactyly Genu recurvatum Hammertoe Medial rotation of the medial malleolus Pes cavus Pes planus Protrusio acetabuli Abnormality of limbs Arachnodactyly Arachnodactyly Genu recurvatum MedGen UID: 2047 •Concept ID: C0003706 Hammertoe •Congenital Abnormality Abnormally long and Medial rotation of the slender fingers ("spider fingers"). medial malleolus See: Feature record | Search on this feature Pes cavus Pes planus Protrusio acetabuli Clinical Trials.gov Molecular resources

Consumer resources Recent systematic reviews Term hierarchy GeneReviews®

 An international point-of-care resource for busy clinicians, provides clinically relevant and medically actionable information for inherited conditions in a standardized journal-style format, covering diagnosis, management, and genetic counseling for patients and their families

 Each chapter in GeneReviews is written by one or more experts on the specific condition or disease and goes through a rigorous editing and peer review process before being published online.

 GeneReviews currently comprises 765 chapters.

 The two general formats for GeneReviews are: chapters focused on a single gene or phenotype (~95%) and overviews summarizing genetic causes of common conditions (e.g., deafness and hearing loss, Alzheimer disease) (~5%). 1- Google search (X GeneReviews) Gene Reviews by Title

New in Gene Reviews GeneReviews

Hereditary Hearing Loss and Deafness Overview FMR1-Related Disorders

 Summary  Summary  Clinical Characteristics of HH Loss and Deafness  Gene Review Scope  Diagnosis  Diagnosing Deafness and Hearing Loss  Clinical Characteristics  Differential Diagnosis of HH Loss and Deafness  Genetically Related (Allelic) Disorders  Causes of Hereditary Hearing Loss and Deafness  Differential Diagnosis  Evaluation Strategy  Management  Genetic Counseling  Genetic Counseling  Resources  Resources  Management  Molecular Genetics  References  References  Chapter Notes  Chapter Notes ClinVar

ClinVar is a freely accessible, public archive of reports of the relationships among human variations and phenotypes, with supporting evidence Clinvar ClinVar

gene symbols, e.g. PTEN HGVS expressions, e.g. NM_000314.4:c.395G>T protein changes, e.g. G132V rs numbers, e.g. rs180177042 diseases, e.g. PTEN hamartoma tumor syndrome submitters, e.g. Invitae a location on a chromosome for an assembly, 10[chr] AND 89623000:89730000[chrpos37]

Review Status

Four Star - Practice guideline Three Star - Reviewed by expert panel Two Star - Multiple submitters, no conflicts • Level of review One Star - Criteria provided, conflicting interpretations One Star - Criteria provided, single submitter None star - No assertion for the individual variant • Clinical significance • Conflicting• interpretationsMolecular consequence(17) • Benign(15)• Frameshift(33) • Likely benign• Missense(23) (165) • Uncertain significance• Nonsense(101)(27) • Likely pathogenic• Splice(49) site(4) • Pathogenic•(101)ncRNA(0) • Risk factor(0)• Near gene(0) • UTR(34) http://simpleclinvar.broadinstitute.org/

'clinvar', a 'disease term', a 'gene name' or a 'variant' in HGVS format

A web server application that is able to provide variant, gene and disease level summary statistics based on the entire ClinVar database in a dynamic and user friendly web interface.

Online Mendelian Inheritance in Man (OMIM)

Updated catalog of human genes and genetic disorders and traits, with particular focus on the molecular relationship between genetic variation and phenotypic expression * gene with known sequence + gene with known sequence and phenotype # phenotype description, molecular basis known % Mendelian phenotype or locus, molecular basis unknown none other, mainly phenotypes with suspected mendelian basis (^) before an entry number means the entry no longer exists

(100000- ) to (200000- ) Autosomal loci or phenotypes (May 15, 1994) (300000- ) X-linked loci or phenotypes (400000- ) Y-linked loci or phenotypes (500000- ) Mitochondrial loci or phenotypes (600000- ) Autosomal loci or phenotypes (after May 15, 1994)

* Gene entries

Location Phenotype Inheritance Xq27.3 Fragile X syndrome XLD

Fragile X tremor/ataxia syndrome XLD

Premature ovarian failure 1 XL # Phenotype entries