Novel FBN1 mutation in a family with inherited Marfan Syndrome: p.Cys2672Arg.

Abstract

Marfan Syndrome is an autosomal dominantly inherited disease seen in 2–3 / 10 000 (Judge and Dietz 2005). Heterozygous mutations in FBN1 encoding fibrillin-1 is responsible for Marfan Syndrome, which disrupts connective tissue causing joint and skeletal disorders, ectopia lentis, aortic root dilation and may lead to fatal aortic insufficiency and aortic dissection (Loeys et al. 2010). Ghent-2 nosology, which provides an algorithm incorporating clinical findings, family history and genetic testing, is commonly used for the diagnosis of Marfan Syndrome (Loeys et al. 2010). Here, we present a novel FBN1 missense mutation in a family with inherited Marfan Syndrome and discuss the utility of Ghent-2 nosology and diagnostic challenges. A 14-year-old boy with malar hypoplasia, down-slanting palpebral fissures, dolichocephaly, mild retrognathia and cardiac insufficiency was referred to Medical Genetics Unit. He scored 11 (>7) on Ghent-2 nosology systemic scoring (Fig. 1A). Echocardiogram showed the presence of mitral valve prolapsus and increased aortic root diameter (z-score: 3.41) (Pettersen et al. 2008). Eye examination and intellectual evaluation were normal. There was no history of easy-bruising, bone fractures or joint dislocations. His 12-year-old brother (IV-2) has matching facial features, but scored 2 (<7) on Ghent-2 nosology systemic scoring. Echocardiogram showed normal aortic root diameter (z-score = 1.01) (Fig. 1A). Their father (III-5) died at 38 years due to sudden aortic dissection, and was never evaluated for Marfan Syndrome. Paternal grandfather (II-1) died as a result of traffic accident at age 65, without any known cardiovascular complaints. His father (I-1) suffered from syncope episodes as frequent as several times a day, indicative of aortic insufficiency, but died at age 82 for unknown reasons. Other distant relatives also had aortic abnormalities (III-7, IV-3) and one died due to aortic dissection (IV-4) (Fig. 1A). In two brothers the only variation in FBN1 was c.8014T>C, which is absent in the unaffected mother (Fig. 1A). It is predicted to cause p.(Cys2672Arg) which disturbs a highly conserved disulfide bridge in 43rd calcium-binding EGF-like domain of fibrillin-1 (Fig. 1B,C). Although father (III-5) was not available for genetic testing, presence of Marfan-like findings in father and distant relatives of him strongly implies inheritance from an affected father. The index (IV-1) fulfills the Ghent-2 nosology criteria for Marfan Syndrome. A missense mutation affecting a conserved cysteine residue, family history of Marfan-like cardiovascular findings, and absence of findings that support other Marfan-like syndromes further confirms the diagnosis, establishing p.(Cys2672Arg) as a novel causative mutation for Marfan Syndrome. In addition, another mutation in Marfan Syndrome affecting the same residue, p.(Cys2672Tyr) has been published previously (Franken et al. 2016). However, the same mutation in his brother (IV-2) is insufficient for diagnosis of Marfan Syndrome, considering low systemic score and normal echocardiogram. Variable expressivity and/or small age of the brother may explain the absence of full clinical findings. A previous study shows the importance of age for appearance of clinical findings by demonstrating that only <25% of individuals with FBN1 mutations have increased aortic diameter by age 17 (Détaint et al. 2010). Thus, considering symptoms may require time to appear, he will be followed-up by annual examinations and echocardiograms. Ghent-2 nosology does not provide a definition for individuals with FBN1 mutations and family history in the absence of clinical findings, but it suggests that these individuals can be referred to as “potential Marfan Syndrome” (Loeys et al. 2010). The diagnosis of “potential Marfan Syndrome” is not uncommon. A study including 354 children <20 years old with FBN1 mutations found that 22% of the subjects were diagnosed as “potential Marfan Syndrome” (Faivre et al. 2012). With lower costs and wider usage of molecular genetic tests, we believe increasingly more individuals will be diagnosed as “potential Marfan Syndrome”. This creates a challenge, especially in the setting of prenatal and preimplantation genetic diagnosis. In these situations, a comprehensive family history becomes at least as important as molecular genetic testing in predicting the effect of a certain mutation. The case presented here is a good example of the importance of family history in evaluating “potential Marfan Syndrome”. Thus, we suggest that evaluation of Marfan Syndrome in families should involve a detailed family history and molecular findings beyond the requirements of Ghent-2 nosology for management of various scenarios of “potential Marfan Syndrome”. We would like to thank the family members for participating in this study. The authors have no conflicts of interest to declare.