Jose Antonio Aragon-Martin

Role of ADAMTSL4 mutations in FBN1 mutation‐negative ectopia lentis patients

Ectopia lentis (EL) is genetically heterogeneous with both autosomal‐dominant and ‐recessive forms. The dominant disorder can be caused by mutations in FBN1, at the milder end of the type‐1 fibrillinopathies spectrum. Recently in a consanguineous Jordanian family, recessive EL was mapped to locus 1q21 containing the ADAMTSL4 gene and a nonsense mutation was found in exon 11 (c.1785T>G, p.Y595X). In this study, 36 consecutive probands with EL who did not fulfill the Ghent criteria for MFS were screened for mutations in FBN1 and ADAMTSL4. Causative FBN1 mutations were identified in 23/36 (64%) of probands while homozygous or compound heterozygous ADAMTSL4 mutations were identified in 6/12 (50%) of the remaining probands. Where available, familial screening of these families confirmed the mutation co‐segregated with the EL phenotype. This study confirms that homozygous mutations in ADAMTSL4 are associated with autosomal‐recessive EL in British families. Furthermore; the first compound heterozygous mutation is described resulting in a PTC and a missense mutation in the PLAC (protease and lacunin) domain. The identification of a causative mutation in ADAMTSL4 may allow the exclusion of Marfan syndrome in these families and guide the clinical management, of particular relevance in young children affected by EL.

A Genotype-Phenotype Comparison of ADAMTSL4 and FBN1 in Isolated Ectopia Lentis

PURPOSE To describe the genotype-phenotype relationship of a cohort of consecutive patients with isolated ectopia lentis (EL) secondary to ADAMTSL4 and FBN1 mutations. METHODS Patients underwent detailed ocular, cardiovascular, and skeletal examination. This was correlated with Sanger sequencing of ADAMTSL4 and FBN1 genes. RESULTS Seventeen patients were examined, including one with ectopia lentis et pupillae. Echocardiography and skeletal examination revealed no sign of systemic disorders associated with EL, in particular Marfan syndrome (MFS). Nine patients (52.9%) were found to have mutations in ADAMTSL4, including four novel nonsense mutations. Four patients (25%) were found to have novel FBN1 mutations, not previously reported as causing classical Marfan syndrome. One additional patient was found to have an FBN1 mutation previously reported in classical MFS. Four patients (25%) were found to have no mutations in either gene. Median age of diagnosis of EL was 35 years in patients with FBN1 mutations and 2 years in patients with ADAMTSL4 mutations (P < 0.01). Mean axial length was 22.74 mm (95% confidence interval [CI]: 21.3-24.2) (FBN1) and 27.54 mm (95% CI: 24.2-30.9) (ADAMTSL4) (P < 0.01). Other ophthalmic features, including corneal thickness and power, foveal thickness, visual acuity, and direction of lens displacement, were similar for both groups. CONCLUSIONS ADAMTSL4 is the most important known causative gene in isolated EL. Mutations in ADAMTSL4 appear to cause earlier manifestation of EL and are associated with increased axial length as compared to FBN1. We suggest that ADAMTSL4 be screened in all patients with isolated EL and that physicians be vigilant for the more severe ocular phenotype associated with mutations in this gene.

The revised ghent nosology; reclassifying isolated ectopia lentis

Inherited ectopia lentis (EL) is most commonly caused by Marfan syndrome (MFS), a multisystemic disorder caused by mutations in FBN1. Historically the diagnosis for patients with EL who have no systemic features of MFS is isolated EL (IEL). However, the Ghent nosology for MFS was updated in 2010 and made some important alterations. In particular, patients with EL and a FBN1 mutation are now categorically diagnosed with MFS, if their mutation has previously been described with aortic dilation/dissection. This carries significant systemic implications, as many patients previously diagnosed with IEL are now reclassified. We provide a review of all published cases of IEL caused by FBN1 mutations over the last 20 years to assess what impact the new Ghent nosology has on these. Indeed, 57/123 probands (46.3%) are now classified as MFS according to the revised Ghent nosology and 37/96 mutations (38.5%) reported to cause isolated EL have also been found in patients with aortic dilation/dissection. These findings suggest that EL caused by mutations in FBN1 is actually part of a spectrum of fibrillinopathies with MFS, and the term ‘IEL’ should be avoided in such cases.

Craniosynostosis with Ectopia Lentis and a Homozygous 20-base Deletion in ADAMTSL4

Craniosynostosis with ectopia lentis has been described five times since 1950 with unknown inheritance and variable phenotype. The patient was diagnosed with right coronal synostosis at age 10 weeks requiring surgery, and bilateral ectopia lentis with high myopia at 10 months. No other family member was affected. There is no known consanguinity within the family. Genetic screening ruled out FBN1, TGFBR2, and the known craniosynostosis hotspots (FGFR2 exon 8 and exon 10 and FGFR3 exon 6) as the cause. A homozygous deletion in exon 6 of ADAMTSL4 (c.767_786del 20) that has been shown to cause isolated ectopia lentis was found. The mutation results in a premature termination codon (p.Gln256ProfsX38). The proband’s mother, father and one sibling are heterozygous carriers of the mutation. This is the first detailed report of a possible genetic determinant of craniosynostosis with ectopia lentis. Although this mutation causes isolated ectopia lentis, this may be evidence of pleiotropic effects of ADAMTSL4 and may represent an overlapping syndrome with a causative mutation in ADAMTSL4. These findings need to be confirmed in further cases with craniosynostosis and ectopia lentis.

Focus on Molecules: ADAMTSL4

The ADAMTSL4 gene (MIM:610113) is a member of the ADAMTSL (A Disintegrin AndMetalloproteinase with Thrombospondin Motifs Like) gene family. It is found on chromosome 1q21 and encodes the 1074 amino acid ADAMTS-Like 4 protein (NP_061905). ADAMTSL4 consists of 17 coding exons and two untranslated exons, which span 11.5 kb of genomic sequence. ADAMTS-Like 4 is one of the family of 7 ADAMTS-Like proteins, themselves part of the Thrombospondin type 1 repeat (TSR) superfamily of proteins. These 7 proteins are divided into two distinct clades, of which ADAMTS-Like 4 and ADAMTS-Like 6 form part of one clade, differing fromADAMTS-Like 1, ADAMTS-Like 3 and ADAMTS-Like 7 by lacking immunoglobulin repeat regions (Apte, 2009). The function and disease associations of these proteins are as yet unknown, and thus comparisons between structure and function remain challenging. ADAMTS proteins comprise a protease domain and an ancillary domain, the latter of which determines substrate recognition and function in tissue specificity. ADAMTS-Like proteins are structurally similar to the ADAMTS ancillary domain, including at least one TSR module. Although the TSR repeats are very closely related, ADAMTS-Like proteins lack the proteolytic domains found in ADAMTS proteins. This homology with the ancillary domain may suggest an inhibitory or enhancer relationship between the ADAMTS-Like and ADAMTS proteins. Alternatively this relationship

Genetic testing in Marfan syndrome.

Genetic testing is aiding rapid diagnosis of Marfan syndrome as a basis for management of eye, heart and skeletal disease. The affected patients mutation can be used as a basis for prenatal or postnatal diagnosis of offspring. Preimplantation genetic diagnosis, the technique of choice, can ensure an unaffected pregnancy.

A mutation in the LMOD1 actin-binding domain segregating with disease in a large British family with thoracic aortic aneurysms and dissections

We describe a mutation in LMOD1, which predisposes individuals to thoracic aortic aneurysms and dissections in a large multi-generation British family. Exome variant profiles for the proband and two distantly related affected relatives were generated and a rare protein-altering, heterozygous variant was identified, present in all the exome-sequenced affected individuals. The allele c.1784T>C, p.(V595A) in LMOD1 is located in a known actin-binding WH2 domain and is carried by all living affected individuals in the family. LMOD1 was further assessed in a consecutive series of 98 UK TAAD patients and one further mutation was found, yielding an incidence of ∼2% in our study group. Assessment of LMOD1 in international TAAD cohorts discovered nine other missense variants of which three were classed as likely pathogenic. Validation of LMOD1 was undertaken using a zebrafish animal model. Knock-down of both lmod1a and lmod1b paralogs using morpholino oligonucleotides showed a reproducible abnormal phenotype involving the aortic arches under off-target controls. Injection of the human LMOD1 c.1784T>C, p.(V595A) mutation demonstrated a likely dominant negative effect and illustrated a loss of function cause. Mutations found in the WH2 actin-binding domain of LMOD1 may delay actin polymerization and therefore compromise actin length, dynamics and interaction with myosin in the smooth muscle contraction pathway.

Marfan Syndrome (MFS): Inherited Microfibrillar Disorder Caused by Mutations in the Fibrillin-1 Gene

There have been several studies suggesting that FBN1 gene was responsible for the Marfan syndrome (MFS) phenotype [1–4] before announcing the localisation of the gene on chromosome 15q21.1 in 1991 [3, 5, 6]. Subsequently, many research laboratories started to screen FBN1 in their MFS patients. Many mutations have been mapped to this gene due to this increase in genetic screening and international collaborations confirming FBN1 as the gene responsible for Marfan syndrome [7–15]. This has been the final proof to confirm that the FBN1 gene is the cause of MFS.

Cardiovascular Management of Adults with Marfan Syndrome

Marfan syndrome (MFS) is a disease in which connective tissue becomes weak secondary to fibrillin-1 mutations, resulting in aortic dilatation, aneurysm formation, aortic dissection, aortic regurgitation and mitral valve prolapse. This autosomal dominantly inherited condition, which was first reported in 1895 and was more fully described in 1931, is characterised by abnormal Fibrillin-1 protein (FBN1) (discovered in 1990), which is encoded by the FBN1 gene (reported in 1991). In the 1970s, the life expectancy of people with MFS was 40-50 years, mainly due to increased risk of aortic dissection or heart failure from aortic or mitral regurgitation. However, due to advances in medical and surgical therapy, life expectancy has improved dramatically and is now comparable to that of the general population. We discuss the cardiac manifestations of MFS, the incidence of arrhythmia in this population, the standard of medical care for arrhythmia and valve insufficiency, and a new use of preventive medication to preserve the integrity of the aortic wall in patients with MFS.

A Genotype-Phenotype Comparison of ADAMTSL4 and FBN1 in Isolated Ectopia LentisADAMTSL4 and FBN1 in Isolated Ectopia Lentis

PURPOSE To describe the genotype-phenotype relationship of a cohort of consecutive patients with isolated ectopia lentis (EL) secondary to ADAMTSL4 and FBN1 mutations. METHODS Patients underwent detailed ocular, cardiovascular, and skeletal examination. This was correlated with Sanger sequencing of ADAMTSL4 and FBN1 genes. RESULTS Seventeen patients were examined, including one with ectopia lentis et pupillae. Echocardiography and skeletal examination revealed no sign of systemic disorders associated with EL, in particular Marfan syndrome (MFS). Nine patients (52.9%) were found to have mutations in ADAMTSL4, including four novel nonsense mutations. Four patients (25%) were found to have novel FBN1 mutations, not previously reported as causing classical Marfan syndrome. One additional patient was found to have an FBN1 mutation previously reported in classical MFS. Four patients (25%) were found to have no mutations in either gene. Median age of diagnosis of EL was 35 years in patients with FBN1 mutations and 2 years in patients with ADAMTSL4 mutations (P < 0.01). Mean axial length was 22.74 mm (95% confidence interval [CI]: 21.3-24.2) (FBN1) and 27.54 mm (95% CI: 24.2-30.9) (ADAMTSL4) (P < 0.01). Other ophthalmic features, including corneal thickness and power, foveal thickness, visual acuity, and direction of lens displacement, were similar for both groups. CONCLUSIONS ADAMTSL4 is the most important known causative gene in isolated EL. Mutations in ADAMTSL4 appear to cause earlier manifestation of EL and are associated with increased axial length as compared to FBN1. We suggest that ADAMTSL4 be screened in all patients with isolated EL and that physicians be vigilant for the more severe ocular phenotype associated with mutations in this gene.