1) The document describes three situations involving the identification of secondary genetic findings from exome sequencing. 2) In the first situation, exome sequencing of a child identified not only the causal diagnosis but also a pathogenic BRCA2 mutation inherited from the father, raising issues around informing the family. 3) The second situation involved identifying a likely pathogenic KCNH2 variation (linked to long QT syndrome) in a patient, necessitating familial screening in the absence of a primary diagnosis. 4) The third situation was a deceased infant where exome sequencing identified a variant of unknown significance related to the condition as well as a pathogenic PSK9 mutation inherited from the unknown father, complicating informing relatives.

1. Role play debate on secondary
findings
Winter school, Eurordis, Paris, 20th March 2018

2. • Helen, 3 years, come to the genetic clinic for the first time for
genetic work up of ID and movement disorders. The parents
have wished to have access to actionnable genetic
presdispotistion. There is no family history and the maternal
family of the father is unknown
• Incidental identification by exome of the causal diagnosis, but
also a pathogenic BRCA2 mutation, inherited from the father
• Informed consent mentionned the possibility of incidental
actionnable finding that will be examined by an ethical
committee
• Results to be transmitted to the family? Question of the
protection of the minor in the absence of risk in childhood
Situation 1

3. • Emily, 20 years, come back for the 8th time at the genetic clinic
for the genetic work-up of a malformative syndrome with
severe limb anomalies, with a strong demand of diagnosis in the
context of a wish of pregnancy. The consent offers the
possibility of having access to actionnable secondary findings
• Exome analysis did not identify a cause for the disorder, but
found a probably pathogenic KCNH2 variation (long QT
syndrome)
• Difficulties in the absence of primary diagnosis and the
identification of a familial risk that will necessitate familial
screening
Situation 2

4. • Alban, died in intensive care at 10 days of life of a
polymalformative syndrome. The mother is alone, the father
have left at the begining of the pregnancy. She has asked to
have access to secondary actionnable finding, before knowing
the severe prognosis of her child.
• The exome identify a variant of unknown significance that might
explain the malformative syndrome, that will necessitate data
sharing. A pathogenic variation also evidenced a pathogenic
PSK9 mutation, not inherited from the mother, responsable for
familial hypercholesterolemia.
• Difficulties in recontacting the father (loi d’information à la
parentèle), which was not the priority for the mother
Situation 3