Mystery(n) Phenotypic Presentation in Europeans: Report of Three Further Novel Missense Variants Leading to Severe Syndromic Forms of Moyamoya Angiopathy and Literature Review.

Claudia Santoro, Giuseppe Mirone, Mariateresa Zanobio, Giusy Ranucci, Alessandra D'Amico, Domenico Cicala, Maria Iascone, Pia Bernardo, Vincenzo Piccolo, Andrea Ronchi, Giuseppe Limongelli, Marco Carotenuto, Vincenzo Nigro, Giuseppe Cinalli, Giulio Piluso

Journal: International journal of molecular sciences 2022;23(16):8952

PMID: 36012218

Free Full Text on MDPI View on PubMed

Abstract

Moyamoya angiopathy (MMA) is a rare cerebral vasculopathy in some cases occurring in children. Incidence is higher in East Asia, where the heterozygous p.Arg4810Lys variant in (Mysterin) represents the major susceptibility factor. Rare variants in have also been found in European MMA patients with incomplete penetrance and are today a recognized susceptibility factor for other cardiovascular disorders, from extracerebral artery stenosis to hypertension. By whole exome sequencing, we identified three rare and previously unreported missense variants of in three children with early onset of bilateral MMA, and subsequently extended clinical and radiological investigations to their carrier relatives. Substitutions all involved highly conserved residues clustered in the C-terminal region of RNF213, mainly in the E3 ligase domain. Probands showed a occurring variant, p.Phe4120Leu (family A), a maternally inherited heterozygous variant, p.Ser4118Cys (family B), and a novel heterozygous variant, p.Glu4867Lys, inherited from the mother, in whom it occurred (family C). Patients from families A and C experienced transient hypertransaminasemia and stenosis of extracerebral arteries. Bilateral MMA was present in the proband's carrier grandfather from family B. The proband from family C and her carrier mother both exhibited annular figurate erythema. Our data confirm that rare heterozygous variants in cause MMA in Europeans as well as in East Asian populations, suggesting that substitutions close to positions 4118-4122 and 4867 of could lead to a syndromic form of MMA showing elevated aminotransferases and extracerebral vascular involvement, with the possible association of peculiar skin manifestations.

Address: Child and Adolescent Neuropsychiatry Clinic, Department of Mental and Physical Health and Preventive Medicine, University of Campania "Luigi Vanvitelli", Via Pansini 5, 80131 Naples, Italy.; Department of Women's and Children's Health, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Via De Crecchio 4, 80138 Naples, Italy.; Department of Neurosciences, Santobono-Pausilipon Children's Hospital, AORN, Via Ravaschieri 8, 80122 Naples, Italy.; Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Via Luigi De Crecchio 7, 80138 Naples, Italy.; Department of Pediatrics, Santobono-Pausilipon Children's Hospital, AORN, Via Ravaschieri 8, 80122 Naples, Italy.; Department of Radiology, Tortorella Private Hospital, Via Aversano 1, 84214 Salerno, Italy.; Laboratory of Medical Genetics, ASST Papa Giovanni XXIII, Piazza OMS 1, 24127 Bergamo, Italy.; Department of Neurosciences, Pediatric Psychiatry and Neurology, Santobono-Pausilipon Children's Hospital, AORN, Via Ravaschieri 8, 80122 Naples, Italy.; Dermatology Unit, University of Campania "Luigi Vanvitelli", Via Pansini 5, 80131 Naples, Italy.; Anatomic Pathology Unit, University of Campania "Luigi Vanvitelli", Piazza Miraglia 2, 80138 Naples, Italy.; Division of Cardiology, Monaldi Hospital, University of Campania "Luigi Vanvitelli", Via Bianchi, 80131 Naples, Italy.; Child and Adolescent Neuropsychiatry Clinic, Department of Mental and Physical Health and Preventive Medicine, University of Campania "Luigi Vanvitelli", Via Pansini 5, 80131 Naples, Italy.; Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Via Luigi De Crecchio 7, 80138 Naples, Italy.; Telethon Institute of Genetics and Medicine, Via Campi Flegrei 34, 80078 Pozzuoli, Italy.

DOI: 10.3390/ijms23168952

Link outs

Free resources

Full Text Sources:

Medical:

https://medlineplus.gov/vasculardiseases.html

MeSH Terms: Child, Female, Humans, Adenosine Triphosphatases, Constriction, Pathologic, Genetic Predisposition to Disease, Moyamoya Disease, Transcription Factors, Ubiquitin-Protein Ligases, Vascular Diseases