Genes and GenomesAll you need to know about genetics.....

Dr Katie Johnson

Specialty Registrar

Nottingham University Hospitals

GIM Teaching27.04.2021

Genetics –Clinical Cases

3.00pm

Case 1

• 30 year old

• Multiple renal cysts and liver cysts

• Normal BP and eGFR>90

Family History

Dialysis at 65

Genetic Testing

• Heterozygous PKD1 c.2917C>T p.(Gln973*)

• Daughter at 50% risk

• Testing of children from 10 years (screening)

• Couple wanted to extend their family

• Options include:

– Natural pregnancy accepting 50% chance of child inheriting PKD1 variant

– Preimplantation Genetic Diagnosis (PGD)

– Prenatal test (CVS or amniocentesis)

Preimplantation Genetic Diagnosis

NHS Funding• The couple must be at risk of having a child with a serious genetic condition.• The couple must have been referred to the PGD provider by a NHS Clinical

Genetics Service• The risk of conceiving a pregnancy affected by a serious genetic condition must be

10% or more• The couple must have received genetic counselling from a clinical geneticist or a

registered genetic counsellor.• The female partner must be under 40 years of age at the time of treatment• The female partner must have a BMI of more than 19 and less than 30.• Both partners must be non smokers• There must be no living unaffected child from the current relationship.• The HFEA must have licensed the indication for PGD.• The test must be included in the list of UK Genetic Testing Network (UKGTN)

approved tests, or be suitable for inclusion.• The couple must not be seeking PGD primarily because they are infertile or for any

other reason be unable to have children on their own.• Couples meeting the above criteria will be eligible to receive up to three cycles

Can we test the 1 year old child?

Dialysis at 65

1 year old

Genetic Testing of Children

• Consider testing if a medical intervention would be offered

• Parental decision making on behalf of their child

• Protecting child’s future autonomy

• Case discussed at our MDT meeting and testing offered

• Child carried familial PKD1 variant

• Referred for PGD

Case 2

• 4 year old referred from ophthalmology with lens dislocation

Aorta =

3.7cm

Z score =

2.52

Aorta =

6.7cm

Dislocated

lens

Family tree

Marfan syndrome

• Diagnosis before complications is compatible with normal life expectancy

• Vast majority of tall, slim young men do not have Marfan syndrome

• If suspecting Marfan – arrange echo requesting Ao diameter at sinus of Valsalva

Emphasis on aortic dilatationand lens dislocation

Mutation analysis included

Index Case, in the absence of a family history• Aortic root dilatation (Z ≥2) or dissection + Ectopia lentis• Aortic root dilatation (Z ≥ 2) or dissection + FBN1 mutation• Aortic root dilatation (Z ≥ 2) or dissection +7 or more systemic points• Ectopia lentis + FBN1 mutation associated with Ao problems

Family member:• Ectopia lentis + FH of MFS (as defined above)• 7 or more systemic points + FH of MFS (as defined above)• Aortic root dilatation (Z≥ 2 if over 20yrs or ≥3 below 20yrs) + FH of

MFS

Systemic Features Score

Wrist AND thumb sign (3) Wrist OR thumb sign (1)

Pectus carinatum (2) Pectus excavatum or chest asymmetry (1)

Hindfoot deformity (2) Pes planus -no hindfoot deformity (1)

Pneumothorax (2)

Dural ectasia (2)

Protrusio acetabuli (2)

US/LS <0.85 AND span/height >1.05 AND no severe scoliosis* (1)

Scoliosis or thoracolumbar kyphosis (1)

Reduced elbow extension <170°(1)

Facial features (≥3/5 – dolichocephaly, enopthalmos, DSPFs, malar hypoplasia, retrognathia) (1)

Skin striae (1)

Myopia >3diopters (1)

Mitral valve prolapse (all types) (1)

NB High arched palate no longer used in assessment !!

Loeys-Dietz syndromeAutosomal dominant; mutation in TGFBR1 or TGFBR2

But if you see this……………..

Case 3

• 39 year old with a known FH of Familial Adenomatous Polyposis (FAP) is referred to Genetics

• Received a TWIMC letter from her brother who had recently been diagnosed with FAP

• Pathogenic variant in APC gene

FAP

• Numerous benign polyps (adenomas) colon/rectum

• Stomach and small bowel can also be affected

• Malignancy often develops in 30s

• Total colectomy and upper/lower endoscopy

• Autosomal Dominant

Pedigree

• Attended clinic appointment

• Some concerns about a positive result and surgery/stoma

• Consented to testing

• Results appointment made which she did not attend

• Unfortunately she had inherited the familial APC variant

What would you do now?

What would you do now?

• A letter was sent offering a further appointment but no response

• What are the considerations for our patient and also her children?

• Can we contact the children’s GP?

• Taken to our national Genethics meeting and we contacted the children’s GP disclosing 50% risk

Practical points• Remember our service exists!

• Ask patients about their family history– Sketch out the family tree

• Offer referral to clinical genetics if your patient:• Has a diagnosis of a known genetic condition (?reproductive

age)

• Has multiple problems but no unifying diagnosis

• Expresses concerns regarding their own family history

• Make urgent referrals (pregnant or terminally patient) by telephone / nhs.net

• Consider storing DNA (EDTA) if your patient is terminally ill/medically unwell

Ring the clinical genetics team & ask to speak to genetic counsellor/doctor

on-call

(0115) 962 7728

City Hospital Campus

or

Email or nuhnt.clinicalgenetics@nhs.net or Call with urgent referrals

(0115) 9628042

(e.g. terminal patients high risk family history)

Not sure whether to refer or not?

Consultant in Clinical GeneticsUniversity Hospitals of LeicesterLeicester Royal InfirmaryLeicester, LE1 5WWPhone: 0116 258 5736Fax: 0116 258 6057

Important to send 4-10 ml blood in the correct tube

EDTA – Molecular Genetics (and microarray)Lithium Heparin - Cytogenetics

and correctly labelled on blood tube and referral cardFull name, dob, NHS/Genetic No

Sample requirements