AB085. Imprinting mutation of CDKN1C in Beckwith-Wiedemann Syndrome: inheritance, genetic counselling and surveillance

Background: Beckwith-Wiedemann Syndrome (BWS), a genetic overgrowth disorder is typified by exomphalos, macroglossia and neonatal gigantism. The molecular basis is known in approximately 80% of patients and is heterogeneous involving epigenetic and genetic changes at chromosome 11p15.5. An uncommon cause is a point mutation at CDKN1C found in approximately 5% of cases. When found, 1/3 of CDKN1C mutation is familial. We describe the first Malaysian family with CDKN1C mutation c.232C > T (Q78X), their clinical features, issues related to genetic counselling and subsequent follow-up.

Case presentation: Fifteen children fulfilling the clinical criteria for the diagnosis of BWS were included in a research study to uncover their genotype. One patient was found to carry the CDKN1C mutation c.232C > T (Q78X). This patient was the first child born to unrelated parents at 30+6/40 gestation. He was large for gestational age with a birth weight of 2.21 kg. He had an exomphalos, bilateral dysplastic kidneys and facial dysmorphism consistent with BWS. After a stormy neonatal period, he succumbed on day 17 of life. Before his molecular analysis was completed, his mother gave birth to a girl at 37+1/40 gestation; birth weight was 3.4 kg. This child was antenatally diagnosed with exomphalos and amniocentesis revealed normal karyotype. At birth, she had facial features of BWS, cleft palate and normal kidneys. Her exomphalos was surgically corrected on day 3 of life, after which she progressed well albeit with mild developmental delay. Their mother is phenotypically normal and carries the said pathogenic CDKN1C mutation. She is currently pregnant with her third child. Genetic counselling was provided and she fully comprehends the recurrence risk of 50% in this pregnancy as well as the availability of prenatal diagnostic testing. Prenatal testing was declined.

Discussion and conclusions: The diagnosis of BWS can be confidently achieved with well-established clinical criteria. However, molecular diagnosis is of utmost importance for accurate genetic counselling because of the high recurrence risk of maternally inherited CDKN1C point mutation. Surveillance on follow-up can also be tailored with the knowledge of molecular diagnosis as CDKN1C mutation is associated with the lowest risk of embryonal tumours commonly associated with the other genotype. In this report, we have shown a phenotypically unaffected mother with a pathogenic CDKN1C mutation. This mutation could have occurred de novo or inherited from her father as it is silent in the paternal allele. In the latter scenario, genetic counselling should be offered to all her sisters so that they may make informed choices with regards to their reproduction.

Keywords: CDKN1C; imprinting; overgrowth