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.
Highlights
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
Implementation of targeted gene panel next-generation sequencing (NGS) in individuals with Heritable connective tissue disorders (HCTD) or hereditary aortopathies in a clinical setting has been proven to be powerful in obtaining a genetic diagnosis: a pathogenic or likely pathogenic variant was identified in 3.9–35.5% of the patients tested in different centers worldwide[18,19,20,21,22,23,24,25,26]
The majority were males (51, 61.5%; CI 95% 51–71) and children and adolescents (53, 64% were less than 18 years of age; CI 95% 53–73)
Summary
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. Marfan syndrome (MFS, MIM#154700), Loeys–Dietz syndrome (LDS, MIM#609192, MIM#610168, MIM#613795, MIM#614816, MIM#615582), and Shprintzen–Goldberg syndrome (SGS, MIM#182212) belong to the HCTDs and share many clinical features, such as cardiovascular, skeletal, craniofacial, ocular, and cutaneous abnormalities[1]. Implementation of targeted gene panel next-generation sequencing (NGS) in individuals with HCTD or hereditary aortopathies in a clinical setting has been proven to be powerful in obtaining a genetic diagnosis: a pathogenic or likely pathogenic variant was identified in 3.9–35.5% of the patients tested in different centers worldwide[18,19,20,21,22,23,24,25,26]. In individuals with clinical features typical of HCTD or with a non-syndromic form of aortopathy an NGS-based molecular test is the most practical screening method to identify the disease-related sequence variant. Our patient cohort is small, this is the first study reporting on the spectrum of variants in FBN1, TGFBR1, TGFBR2, and SKI in Indian individuals, with about 50% novel pathogenic variants
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