ESPE2021 Young Investigators Young Investigators (5 abstracts)
Identification of novel genetic causes of familial central precocious puberty
Magdalena Avbelj Stefanija 1,2 , Jernej Kovač 3 , Galia Gat-Yablonski 4,5,6 , Eva Novak 3 , Tinka Hovnik 3 , Alma Toromanović 7 , Gordana Stipančič 8 , Tatjana Milenković 9 , Rade Vuković 9 , Slađana Todorović 9 , Aleksandra Jančevska 10 , Vera Zdravković 11 , Maja Jesič 11 , Sandra Stanković 12 , Moshe Phillip 13,6 , Tadej Battelino 1,2 & Liat de Vries 13,6
1University Medical Centre Ljubljana, University Children’s Hospital, Department for Pediatric Endocrinology, Diabetes and Metabolism, Ljubljana, Slovenia.;2Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.;3University Medical Centre Ljubljana, University Children’s Hospital, Unit for Special Laboratory Diagnostics, Ljubljana, Slovenia.;4Felsentein Medical Research Center, Petah Tikva, Israel.;5The Jesse Z and Sara Lea Shafer Institute for Endocrinology and Diabetes, Schneider Children’s Medical Center of Israel, Petah TIkva, Israel.;6Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;7University Clinical Centre Tuzla, Tuzla, Bosnia and Herzegovina.;8University Hospital Centre Sestre Milosrdnice, Zagreb, Croatia.;9Institute for Health Protection of Mother and Child of Serbia, Belgrade, Serbia.;10University Children’s Hospital Skopje, Skopje, Republic of Macedonia.;11University Children‘s Hospital Tiršova, Belgrade, Serbia.;12Clinic for Childrens Internal Disease, Clinical Center Niš, Niš, Serbia.;13The Jesse Z and Sara Lea Shafer Institute for Endocrinology and Diabetes, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel
Introduction: The major genetic cause of CPP is the paternally inherited Makorin RING-finger protein 3 (MKRN3) deficiency. Rare patients carry variants in kisspeptin and its receptor and DLK1.
Objectives: To identify genetic causes of CPP.
Population and methods: MKRN3 Sanger sequencing was performed in 56 unrelated subjects (12 familial non-maternal, 44 sporadic (6 boys)), whole-genome sequencing (WGS) in 15 family trios (10 maternal), and whole-exome sequencing (WES) in 38 probands (13 familial maternally, 5 sporadic boys, 20 sporadic girls - CPP before 7 years).
Results: Pathogenic MKRN3 variants were identified 5/12 familial subjects (42%), including a novel missense variant, none in sporadic patients. In the coding regions of 398 genes associated with age at menarche on average 25 rare (MAF<0.2%) variants/person were identified; however, genetic landscape varied greatly between patients. No DLK1 variants were detected. In genes associated with hypogonadotropic hypogonadism (HH) 17 rare and predicted pathogenic coding missense or nonsense variants were found heterozygous. Some of them were previously associated with HH, including p.Q106R in GNRHR, p.H83R in TAC3, p.A194D and p.C389X in KISS1R and p.L173R in PROKR2 gene. Rare (MAF<0.025%) predicted pathogenic variants in axon guiding pathway SEMA3/NRP/PLXNA, which is relevant for GnRH neuron migration, were more frequent in our cohort as compared to a general population, yet evenly distributed across genes.
Conclusions: MKRN3 variants were common in non-maternal familial CPP. Certain HH variants tolerated CPP. Potentially pathogenic variants in axon guiding pathway seem to be overrepresented in the CPP cohort as compared to the general population, which should be verified by testing a larger cohort and addressing the mechanisms.
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