Weill-Marchesani-like Syndrome Caused by an FBN1 Mutation with Low-Penetrance
Weill-Marchesani syndrome (WMS) is a rare connective tissue disorder characterized by a distinct set of clinical features, including brachydactyly, short stature, joint stiffness, cardiovascular abnormalities, and various ocular anomalies such as microspherophakia, cataracts, ectopia lentis, myopia, and secondary glaucoma. In cases where patients exhibit incomplete or atypical manifestations of WMS, the condition is often referred to as Weill-Marchesani-like syndrome (WMS-like). The genetic basis of WMS is heterogeneous, with both autosomal dominant (AD) and autosomal recessive (AR) inheritance patterns reported. However, distinguishing between these modes of inheritance based solely on clinical findings is challenging due to the overlapping phenotypes and the variable expressivity of the disease. This study presents a detailed genetic and clinical analysis of a Chinese family affected by AD WMS-like syndrome caused by a heterozygous mutation in the fibrillin-1 gene (FBN1), highlighting the clinical heterogeneity and low penetrance associated with this mutation.
Clinical Presentation of the Family
The study focuses on a three-generation Chinese family with multiple members exhibiting features consistent with WMS-like syndrome. The proband, a 68-year-old man (I-1), presented with significant ocular abnormalities, including downward lens dislocation in both eyes, which precluded accurate measurement of his refractive status. His visual acuity was severely impaired, measuring 20/500 in the right eye (OD) and 20/200 in the left eye (OS). Despite the lens dislocation, his axial lengths were within normal range (23.21 mm in OD and 23.23 mm in OS), and his corneal refractive power was also normal. Elevated intraocular pressure (30 mmHg) was noted in the right eye, while the left eye exhibited normal pressure (17.9 mmHg). Slit lamp microscopy revealed no evidence of microspherophakia, but the patient exhibited brachydactyly and short stature (163 cm). No joint stiffness or cardiac abnormalities were observed. Based on the combination of ectopia lentis, brachydactyly, and short stature, he was diagnosed with WMS-like syndrome.
The proband’s 47-year-old daughter (II-1) also exhibited features of WMS-like syndrome. Slit lamp examination revealed upward lens luxation and coloboma in the lower part of the lens. Unlike her father, she had significantly longer axial lengths (28.71 mm in OD and 25.96 mm in OS), which contributed to her high myopia. Her intraocular pressure was normal (15 mmHg in OD and 13 mmHg in OS), and she also displayed brachydactyly and short stature (150 cm).
The third affected family member was the 17-year-old grandson (III-3) of the proband. He presented with mild posterior lens opacity but no evidence of lens luxation. His lens thickness was normal (3.31 mm in OD and 3.30 mm in OS), and his axial lengths were within the normal range (24.04 mm in OD and 24.56 mm in OS). Unlike his grandfather and mother, he did not exhibit brachydactyly or short stature, standing at 170 cm. No microspherophakia, joint stiffness, or cardiac abnormalities were observed in any of the family members.
Genetic Analysis and Mutation Identification
Whole-exome sequencing (WES) was performed on the proband’s daughter (II-1) to identify the genetic cause of the WMS-like syndrome in the family. The analysis revealed a heterozygous intronic mutation (c.1327+1G>A) in the FBN1 gene, which was suspected to be the causative mutation. This mutation was located within 5 base pairs of a splicing junction, suggesting that it could disrupt normal splicing and result in an aberrant transcript of the gene. The mutation was confirmed in the proband (I-1) and his grandson (III-3) through Sanger sequencing, while the unaffected family members (II-2, III-1, and III-2) were homozygous for the wild-type allele (GG).
The FBN1 gene encodes fibrillin-1, a large glycoprotein that forms microfibrils in connective tissues. Mutations in FBN1 are known to cause structural or functional abnormalities in connective tissue, leading to a range of clinical manifestations. The identified mutation (c.1327+1G>A) has been previously reported in a white British individual with isolated ectopia lentis, but the clinical presentation in that case was limited to lens subluxation without musculoskeletal or cardiovascular involvement. In contrast, the proband in this study exhibited additional features such as short stature and brachydactyly, underscoring the clinical heterogeneity associated with FBN1 mutations.
Clinical Heterogeneity and Low Penetrance
The clinical heterogeneity observed in this family is a notable aspect of the study. While the proband exhibited downward lens subluxation, short stature, and brachydactyly, his daughter (II-1) presented with upward lens luxation and coloboma, along with significantly longer axial lengths. The grandson (III-3), who also carried the FBN1 mutation, displayed only mild posterior lens opacity with no other significant abnormalities. This variability in clinical presentation within the same family highlights the low penetrance of the FBN1 mutation and the potential for late-onset manifestations.
The low penetrance of the mutation is particularly evident in the case of III-3, who, at 17 years of age, exhibited only mild congenital cataracts with no other signs of WMS-like syndrome. It is possible that he may develop additional symptoms later in life, emphasizing the importance of long-term follow-up in individuals with FBN1 mutations. The mild phenotypic presentation in III-3 also raises the possibility of underdiagnosis, as his condition could easily be overlooked without genetic testing.
Implications for Genetic Counseling and Diagnosis
The findings of this study have important implications for genetic counseling and the diagnosis of WMS-like syndrome. The identification of an FBN1 mutation in this family expands the spectrum of clinical manifestations associated with this gene and underscores the need for comprehensive genetic testing in individuals with suspected WMS or WMS-like syndrome. The low penetrance and variable expressivity of FBN1 mutations can complicate the diagnosis, particularly in cases where the clinical presentation is mild or atypical.
Genetic counseling should take into account the possibility of late-onset manifestations and the potential for asymptomatic carriers within affected families. The identification of the FBN1 mutation in this family also highlights the importance of intronic sequence analysis, as mutations in non-coding regions can have significant functional consequences.
Conclusion
This study reports a Chinese family with AD WMS-like syndrome caused by a heterozygous intronic mutation (c.1327+1G>A) in the FBN1 gene. The clinical heterogeneity and low penetrance observed in this family underscore the complexity of diagnosing WMS-like syndrome and the importance of genetic testing in confirming the diagnosis. The findings also expand the clinical spectrum associated with FBN1 mutations and highlight the need for careful genetic counseling and long-term follow-up in affected individuals.
doi.org/10.1097/CM9.0000000000001406
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