Screening & Genetic Counselling for Sickle Cell Disease

Carleigh Robertson, MSc, CGC

The Fred A. Litwin Family Centre in Genetic Medicine

University Health Network, Toronto ON

Outline• What is Genetic Counselling?

• Genetics 101

• Genetic Basis of Sickle Cell Disease (SCD)

• What is Screening?

• Newborn Screening for SCD

• Maternal Screening for SCD

• Other Resources

• Questions?

What is Genetic Counselling?• Genetic counsellors “…work as members of a healthcare team,

providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions”

• A typical session involves:

Reviewing medical and family history

Physical examination by geneticist

Discussion of the condition, options for testing (if available), implications for family members

Review of ongoing medical care, community support, additional referrals

• Referrals to Genetics can be made by family doctors or specialists

Genetics of Sickle Cell Disease• Caused by change in one of the chemical “letters” within

the HBB gene (11p15.4)

Provides instructions for producing β-globin – one of the subunits of hemoglobin (along with α-globin)

At least one HbS allele (Glu6Val) + a second pathogenic HBBgene variant

• Different types of SCD depending on 2nd gene variant

Hb S/S (ie. homozygous Glu6Val variants) accounts for 60-70% of cases in USA

Other examples: Hb S/C, Hb S/β+-thalassemia

Anemija.rs

Pro ProGlu Glu GluVal

Adapted from beyondthedish.wordpress.com

– CCT – GAG – GAG –

– GGA – CTC – CTC –

– CCT – GTG – GAG –

– GGA – CAC – CTC –DNA

Protein

Hemoglobin

Red Blood

Cell

UNAFFECTED SICKLE CELL DISEASE

X X

X X XX

Screening for Sickle Cell Disease

What is Screening?• Screening: strategy used to identify asymptomatic or pre-

symptomatic individuals who are at risk for specific health problem(s); not diagnostic

Gov.uk

Newborn Screening for SCD• Newborn screening: test performed shortly after birth to

screen for treatable diseases that are asymptomatic in the newborn period

• Standard of care for all babies born in Ontario; not mandatory, however

Coordinated by Newborn Screening Ontario (NSO)

• Screens for:

Metabolic conditions, endocrine conditions, cystic fibrosis, severe combined immunodeficiency (SCID), critical congenital heart disease

Hemoglobinopathies: Hb S/S, Hb S/C, and Hb S/β-thalassemia

Newborn Screening for SCD• High-performance liquid chromatography (HPLC) used to

screen for hemoglobinopathies

Primary target is SCD

Will also detect HbC/D/E disease and Hb Barts (α-thal)

• Results: screen positive or screen negative

Screen negative = low risk of having any of the diseases screened

Screen positive = higher chance of being affected (but not a diagnostic result)

Babies who screen positive are referred to specialist for further testing and follow-up

Newborn Screening for SCD• Hemoglobinopathy carrier status is not typically included

in screening report, but can be requested from NSO

Reasons for Knowing Child’s

Carrier Status

Reasons for Not Knowing

Child’s Carrier Status

Planning for future pregnancies Increased parental worry

Child’s future reproductive

choices

Not an urgent result

Informing other family members Other ways to determine carrier

status later in life

Doesn’t screen for all

hemoglobinopathies

Adapted from newbornscreening.on.ca

Maternal Screening for SCD• Hemoglobin electrophoresis – common method

Mun.ca

Maternal Screening for SCD• Hemoglobin electrophoresis

HbS as sole adult β-chain → Hb S/S or Hb S/β0-thalassemia

HbS plus additional β-chain variant (eg. HbC, HbD, etc.) → compound heterozygosity for specific HBB pathogenic variants

• Complete blood count (CBC) and reticulocyte count

Mean cell volume (MCV) will be normal in Hb S/S, but may be decreased in other forms of SCD

• If SCD has been molecularly confirmed in a close relative, genetic testing for the detected variant(s) may be offered to at-risk family members

Prenatal Testing for SCD• Once HBB pathogenic variants have been identified in

affected family member(s), prenatal testing for SCD is possible

Both disease-causing mutations would need to be identified

Test would be diagnostic, rather than screening

• Prenatal diagnosis typically done via:

Amniocentesis

Chorionic Villus Sampling (CVS)

• Referral to Prenatal Genetics clinic recommended

For More Information• Canadian Association of Genetic Counsellors – www.cagc-

accg.ca

• National Society of Genetic Counselors – www.nsgc.org

• Newborn Screening Ontario – www.newbornscreening.on.ca

• GECK-KO (Genetics Education Canada – Knowledge Organization) – www.geneticseducation.ca

• Genetics Home Reference – www.ghr.nlm.nih.gov

123RF.com

Questions?

References1. Bender MA. Sickle Cell Disease. 2003 Sep [Updated 2017 Aug 17]. In: Adam MP, Ardinger HH,

Pagon RA, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.

2. National Health Service. 2017. NHS Sickle Cell & Thalassaemia Screening Programme. Standards and Guidelines. Third Edition. Accessed 2018 Oct. www.gov.uk.

3. National Heart, Lung, and Blood Institute. 2014. Evidence-Based Management of Sickle Cell Disease: Expert Panel Report. Accessed 2018 Oct. www.nhlbi.nih.gov.

4. Newborn Screening Ontario. Accessed 2018 Oct. www.newbornscreening.on.ca.

5. Newborn Screening Ontario. 2018 Feb. “Newborn Screening Manual: A Guide for Newborn Care Providers” (PDF). Edition 2.1. Ottawa (ON): Accessed 2018 Sept. www.newbornscreening.on.ca.

6. Newborn Screening Ontario. 2018 Oct. Personal communication with NSO staff.

7. Wilson, JMG; Jungner, G. 1968. "Principles and practice of screening for disease" (PDF). WHO Chronicle. Geneva: World Health Organization. 22 (11): 473. Public Health Papers, #34.