Clinically relevant variants in a large cohort of Indian patients with Marfan syndrome and related disorders identified by next-generation sequencing.

Abstract

Marfan syndrome and related disorders are a group of heritable connective tissue disorders and share many clinical features that involve cardiovascular, skeletal, craniofacial, ocular, and cutaneous abnormalities. The majority of affected individuals have aortopathies associated with early mortality and morbidity. Implementation of targeted gene panel next-generation sequencing in these individuals is a powerful tool to obtain a genetic diagnosis. Here, we report on clinical and genetic spectrum of 53 families from India with a total of 83 patients who had a clinical diagnosis suggestive of Marfan syndrome or related disorders. We obtained a molecular diagnosis in 45/53 (85%) index patients, in which 36/53 (68%) had rare variants in FBN1 (Marfan syndrome; 63 patients in total), seven (13.3%) in TGFBR1/TGFBR2 (Loeys-Dietz syndrome; nine patients in total) and two patients (3.7%) in SKI (Shprintzen-Goldberg syndrome). 21 of 41 rare variants (51.2%) were novel. We did not detect a disease-associated variant in 8 (15%) index patients, and none of them met the Ghent Marfan diagnostic criteria. We found the homozygous FBN1 variant p.(Arg954His) in a boy with typical features of Marfan syndrome. Our study is the first reporting on the spectrum of variants in FBN1, TGFBR1, TGFBR2, and SKI in Indian individuals.

• Authors: Shalini S Nayak, Pauline E Schneeberger, Siddaramappa J Patil, Karegowda M Arun, Pujar V Suresh, Viralam S Kiran, Sateesh Siddaiah, Shreesha Maiya, Shrikanth K Venkatachalagupta, Neethukrishna Kausthubham, Fanny Kortüm, Isabella Rau, Alexandra Wey-Fabrizius, Lotte Van Den Heuvel, Josephina Meester, Lut Van Laer, Anju Shukla, Bart Loeys, Katta M Girisha, Kerstin Kutsche
• Journal: Scientific reports (Sci Rep) Vol. 11 Issue 1 Pg. 764 (01 12 2021) ISSN: 2045-2322 [Electronic] England
• PMID: 33436942 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• FBN1 protein, human
• Fibrillin-1
• Proto-Oncogene Proteins
• SKI protein, human
• Receptor, Transforming Growth Factor-beta Type I
• Receptor, Transforming Growth Factor-beta Type II
• TGFBR1 protein, human
• TGFBR2 protein, human

Topics

• Adolescent
• Adult
• Child
• Child, Preschool
• Cohort Studies
• DNA-Binding Proteins (genetics)
• Female
• Fibrillin-1 (genetics)
• Genetic Predisposition to Disease
• High-Throughput Nucleotide Sequencing (methods)
• Humans
• India (epidemiology)
• Infant
• Male
• Marfan Syndrome (epidemiology, genetics, pathology)
• Middle Aged
• Mutation
• Proto-Oncogene Proteins (genetics)
• Receptor, Transforming Growth Factor-beta Type I (genetics)
• Receptor, Transforming Growth Factor-beta Type II (genetics)
• Young Adult