Abstract
AIM
To explore the phenotype and genotype of Weill-Marchesani syndrome (WMS) in a Chinese family and review related literature.
METHODS
Three WMS patients and other unaffected individuals in this family with a history of consanguineous marriage were included in this study. Medical history, comprehensive ophthalmic examinations, and systemic evaluation, as well as whole exome and Sanger sequencing of specific genomic regions, were performed.
RESULTS
The three affected siblings presented with short stature, brachydactyly and ocular disorders, including very shallow anterior chamber, high myopia, microspherophakia lens subluxation with stretched zonules and glaucoma. Genetic analysis verified a homozygous missense mutation (c.2983C>T: p. Arg995Trp) in ADAMTS17, which was correlated with the diseases in this family, indicating an autosomal recessive inherited manner of WMS. This review aims to summarize the mutation sites of WMS genes, so as to prevent the disease and better guide clinical diagnosis and treatment.
CONCLUSION
A novel homozygous missense variant of ADAMTS17 is identified in a WMS family with a history of consanguineous marriage. Our study expands the range of mutations associated with WMS and deepens our understanding of pathology in disease associated with ADAMTS17 variants.
Keywords: Weill-Marchesani syndrome, ADAMTS17, missense variation, molecular genetics
INTRODUCTION
Weill-Marchesani syndrome (WMS) is a rare hereditary connective tissue disease characterized by ocular problems, including microspherophakia, ectopia lentis, high myopia, and secondary glaucoma. Other symptoms include short stature, brachydactyly, joint stiffness, and occasional cardiac defects. The syndrome usually involves a family history or a history of consanguinity between parents or close relatives. WMS can show autosomal dominant or autosomal recessive inheritance. The most common pathogenic genes linked to WMS are the FBN1, LTBP2, ADAMTS10 and ADAMTS17 genes[1]–[8]. Regardless of which of these genes is varied in WMS patients, the disease features appear to be similar. Here, we report a new homozygous variation in ADAMTS17 (MIM*607511, ADAM metallopeptidase with thrombospondin type 1 motif, 17) leading to autosomal recessive WMS in a Chinese family.
SUBJECTS AND METHODS
Ethical Approval
This study followed the principles of the Declaration of Helsinki, and it was approved by the Ethics Committee of West China Hospital of Sichuan University (2019, No.53). All subjects fully understood the purpose of the study and provided written informed consent.
Patient Ascertainment and Clinical Assessment
The proband and other family members were invited to our hospital for a detailed medical history inquiry and complete physical and ophthalmic examination, including height measurement, ECG, hands and feet X-ray, cardiac ocular ultrasound, best-corrected visual acuity testing, intraocular pressure (IOP) measurement (Goldmann tonometry), slit lamp examination, fundus examination, gonioscopy, ultrasound biomicroscopy (UBM), corneal endothelial cell count, B-ultrasound, ocular biometry measurement, visual field and anterior segment-optical coherence tomography (AS-OCT, Cirrus HD-OCT 4000) testing.
Whole-Exome Sequencing and SANGER Sequencing
Peripheral venous blood (3 mL) was collected from each family member for DNA extraction and genotyping. The exons and adjacent splicing regions (approximately 20 base pairs) of the target gene and the full length of the mitochondrial genome were captured and enriched by probe hybridization. The enriched genes were quality controlled and sequenced using a high-throughput sequencer. According to the selected mutation sites, the consolation of other family members was verified.
Bioinformatic Analysis
Sequences of the wild-type ADAMTS17 gene and encoded protein were downloaded from the National Center for Biotechnology Information (NCBI, https://www.ncbi.nlm.nih.gov/), and mutated amino acids in the ADAMTS17 protein were changed manually. The online Cobalt tool (https://www.ncbi.nlm.nih.gov/tools/cobalt) was used to align ADAMTS17 proteins from different species to determine whether a mutated position was conserved. The potential functional implications of ADAMTS17 mutations were predicted using PolyPhen2 (http://genetics.bwh.harvard.edu/pph2/) and SIFT (http://provean.jcvi.org/). The structures of mutant ADAMTS17 proteins were modeled based on homology with the wild-type protein in PyMOL (https://swiss-model.expasy.org).
RESULTS
Family Characteristics
This case study involved a family of nine members, all Han Chinese, from three generations identified at West China Hospital of Sichuan University. Three of the individuals were diagnosed with WMS, including one male (IV-3) and two females (IV-2 and IV-5; Figure 1). The proband was a 22-year-old patient IV-3, who was referred to our clinic with complaints of decreased vision accompanied frequently by eye soreness in both eyes for 5y. He was diagnosed with bilateral secondary angle-closure glaucoma. His sister IV-5 had high myopia in both eyes that was not corrected by glasses and complained of eye soreness after reading for long periods. The other sister, IV-2, had poor visual acuity but never visited the hospital before. Their parents (III-1 and III-2) were in consanguineous marriage. The inheritance pattern of WMS in this family was autosomal recessive. The family pedigree is depicted in Figure 1.
Figure 1. Pedigree showing inheritance of WMS in a Han Chinese family with a history of consanguineous marriages.
Black identifies individuals diagnosed with the syndrome. The arrow marks the proband, IV-3. WMS: Weill-Marchesani syndrome.
The height of the three affected siblings was significantly lower than that of other family members. The other systemic abnormalities included brachydactyly but had no anomalies in the cardiovascular system (Table 1, Figure 2). Ophthalmic examination revealed high myopia, a very shallow anterior chamber, microspherophakia with stretched zonules, lens subluxation and angle closure glaucoma (Figure 3). Their clinical findings are summarized in Table 1. Based on these findings, the proband and his sister (IV-5) underwent surgeries for removal of the dislocated lens and implantation of an intraocular lens (IOL). Capsular bag stabilization was accomplished with capsular hooks during the procedure, and a capsular tension ring was inserted prior to IOL implantation in the capsular bag. Following surgery, visual acuity significantly improved, and the IOP was normalized with a stable, deepened anterior chamber.
Table 1. Clinical features of the affected individuals in the family.
| Characteristic | IV-3 (proband) | IV-2 | IV-5 |
| Gender | Male | Female | Female |
| Age ranges (y) | Early 20s | Early 30s | 10s |
| Best corrected visual acuity (R/L) | 0.15/0.4 | Counting figures/counting figures | 0.5/0.4 |
| The highest intraocular pressure (R/L, mm Hg) | 45/43 | 38/36 | 27/28 |
| Axial length (R/L, mm) | 22.35/22.07 | NA | 20.71/20.87 |
| Anterior chamber of depth (R/L, mm) | 1.46/1.30 | NA | 1.52/1.48 |
| Cup disc ratio (R/L) | 0.9/0.9 | 1.0/1.0 | 0.5/0.5 |
| Myopia (R/L, diopter) | -16.0/-15.0 | -13.0/-13.5 | -11.0/-12.0 |
| Other ocular history | Blurred vision and soreness | NA | Soreness after reading for long periods |
| Height (cm) | 150 | 130 | 128 |
| Brachydactyly | Yes | Yes | Yes |
| Cardiac anomalies | No | No | No |
| Joint stiffnessa | No | No | No |
L: Left eye; NA: Not available; R: Right eye. aBased on the ability to make a fist.
Figure 2. Clinical features of patients.
A: Images of the hands of proband IV-3 and sister IV-5 showing short fingers; B: X-ray of both hands showing a shorter phalanx normal joint.
Figure 3. Ophthalmological characterization of the proband (IV-3).
A: Slit-lamp examination revealed a very shallow anterior chamber in both eyes; B: Anterior segment photographs, after dilatation of the pupil, showing a small spherical lens and a gold ring, which was caused by the reflection of light from the 360° periphery of the small crystalline globular lens with stretched zonules, resulting in the subluxation of the lens; C: UBM showed a shallow anterior chamber in both eyes, a forward-shifted lens iris, and a spherical anterior surface on the lens; D: The AS-OCT, before (a) and after (b) dilatation of the pupil (left eye), showed a very shallow anterior chamber and a subluxated small spherical lens, and the zonules were still not relinquished; E: Fundoscopy showed advanced glaucomatous cupping in both eyes.
Genotyping
A homozygous missense variation c.2983C>Tp.Arg995Trp) was detected in the ADAMTS17 gene in all members of the family with the disease. Individuals III-1, III-2, IV-1, IV-6, and V-1 were heterozygous for the same mutation. One individual was homozygous for the wild-type allele. This mutation changed C2983 to T in the cDNA, resulting in an Arg995Trp substitution in the protein (Figure 4).
Figure 4. Partial sequencing of the ADAMTS17 gene in WMS patients of the family.
A homozygous missense mutation (c.2983C>T: p. Arg995Trp, red arrow) was found in the ADAMTS17 gene of all patients in this family. WMS: Weill-Marchesani syndrome.
Bioinformatics Analysis
The 995Arg position of the ADAMTS17 protein (NP_620688.2) is extremely conserved among different species, such as humans (Homo sapiens), mice (Mus musculus), zebrafish (Danio rerio), frogs (Xenopus tropicalis), rhesus monkeys (Macaca mulatta), rats (Rattus norvegicus), chickens (Gallus gallus), goats (Capra hircus), rabbits (Oryctolagus cuniculus) and hamsters (Cricetulus griseus), according to the alignment of protein sequences shown in Figure 5. The PolyPhen-2 analysis results showed that the missense ADAMTS17 variant (c.2983C>T: p.Arg995Trp) was predicted to be PROBABLY DAMAGING with a score of 1000. The PROVEAN score was -4.928, deleterious, according to the PROVEAN prediction results. Two protein functional prediction tools obtained the same harmful results, indicating that this variant should be pathogenic. Furthermore, the structural prediction results of PyMOL showed that there might be no large structural change between the mutated and wild-type ADAMTS17 proteins. However, the charged and hydrophobic status should be changed at the 995 position, as shown by the black arrows in Figure 5.
Figure 5. Bioinformatics analysis.
A: Protein sequence alignment at the 995 position (red box) among different species; B: Structural modeling by PyMOL showing charged and hydrophobic status. a: Charged wild type; b: Charged mutated protein; c: Hydrophobic wild type; d: Hydrophobic mutated; Black arrow: Mutated position.
DISCUSSION
In this study, we identified a novel homozygous ADAMTS17 missense variant (c.2983C>T: p.Arg995Trp) associated with WMS. Three of nine siblings in the family were diagnosed with WMS.
The proband and his two affected sisters presented with angle closure glaucoma. The proband and one of his sisters (IV-2) showed optic atrophy. Another sister (IV-5) did not exhibit obvious optic atrophy. The reason for the inconspicuous optic atrophy was that she was the youngest and had a short onset time.
To prevent further injury of the optic nerve and improve visual acuity, two affected individuals (proband and IV-5) underwent surgeries to remove the dislocated lens and implant the IOL. In this case, to remove the lens more safely and with less risk of further zonular damage, iris retractors were used to temporarily support and stabilize the capsular bag; then, a capsular tension ring was inserted prior to IOL implantation in the bag. The surgeries were uneventful, and the patients were doing well.
Pathogenic ADAMTS17 variants were first reported in 2009[3]. To date, eight variations in the human ADAMTS17 gene have been reported, including a nonsense mutation (c.1051A>T), a missense mutation (c.760C>T), c.1027A>G, splice-site mutations (c.873+1G>T and c.1721+1G>A), indels (including c.2458_2459insG, c.652delG and a 106.96 Kb deletion containing exon 1–3 regions. Our study increases the number of variations of this gene to nine (Table 2)[1],[3],[9]–[12].
Table 2. Summary of clinical phenotypes of known ADAMTS17 variations linked to WMS.
| Variation |
ADAMTS17 variations |
||||||||
| 106.96-kb deletion[9] | c.652 delG[10] | c.760 C>T[3] | c.873+1 G>T[11] | c.1027 A>G[12] | c.1051 A>T[1] | c.1721+1 G>A[3] | c.2458_2459insG[3] | c.2983C>T | |
| No. of cases, gender | 4, F(4) | 2, F(1), M(1) | 2, F(2) | 1, F(1) | 1, F(1) | 3, F(2), M(1) | 1, M(1) | 4, F(2), M(2) | 3, F(2), M(1) |
| Nationality | Tunisian | Saudi | Saudi | Indian | French Canadian | Chinese | Saudi | Saudi | Chinese |
| Age ranges (years at the time of the study) | Early 20s | 10s | Early 40s | Early 20s | 50s | 20s | 30s | 10s | 10s |
| Average diopters (D) | -6.7 | -9.7 | -7 | -10 | NA | NA | -11.9 | -10.5 | -13.5 |
| Average axial length (mm) | NA | 22.7 | 21.2 | 22.1 | NA | NA | 21.3 | 22.5 | 21.5 |
| Shallow anterior chamber | NA | 1/2 yes, 1/2 no | Yes | NA | NA | Yes | Yes | 3/4 yes, 1/4 no | Yes |
| Microspherophakia | NA | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes |
| Brachydactyly | 3/4 yes, 1/4 no | No | No | Yes | Yes | Yes | No | No | Yes |
| Joint stiffness | 2/4 yes, 2/4 no | No | No | No | No | NA | No | No | No |
| Heart abnormalities | 3/4 yes, 1/4 no | NA | No | No | No | No | No | No | No |
F: Female; M: Male; NA: Not available.
None of the three individuals with WMS in our study showed joint stiffness or cardiac abnormalities, consistent with the lack of such symptoms in other reports of WMS associated with ADAMTS17 variants (Table 2). Review the literature, all the patients had ocular abnormalities and short stature, but only a few patients had brachydactyly, joint stiffness, and cardiac abnormalities. Cardiac abnormalities were reported in only 3 of 18 patients. One of the patients had concomitant tachycardia, mitral valve dysplasia, and cardiomyopathy, and two patients had mitral valve dysplasia[9] Our study adds to the range of ADAMTS17 polymorphisms in humans (Table 2). Further studies should examine whether WMS associated with ADAMTS17 variants represents a different subtype of the disease or simply a milder manifestation of the typical disease phenotype.
ADAMTS17, located at position 15q26.3 (MIM 613195), encodes a member of the ADAMTS family of secreted metalloproteases, which are involved in extracellular matrix (ECM) formation, remodeling and degradation[13]. ADAMTS17, which in the eye is expressed mainly near the crystal epithelium, appears to promote ECM formation, especially the assembly of fibrillin microfibrils[2],[11]. ADAMTS17 appears to stabilize zonular microfibrils[14]; therefore, deficiency in the protein may destabilize microfibrils, causing abnormalities in the lens zonule[12],[14]. Consistent with this idea, polymorphisms in ADAMTS17 have been linked to primary open angle glaucoma and ectopia lentis in dogs[15]–[16]. Future studies should explore the role of ADAMTS17 polymorphisms in the pathogenesis of WMS.
Short stature is a distinct feature of WMS, and ADAMTS17 polymorphism in humans was linked to height[17], as have variations in copy number at a locus near this gene[18]–[19]. ADAMTS17 polymorphism has also been linked to height in dogs[15]–[16], suggesting that ADAMTS17 plays an important role in normal growth and development.
In this study, we analyzed the gene variation in the adjacent splicing region of the whole exome of the proband and revealed a homozygous missense variant c.2983C > T: p. Arg995Trp on the ADAMTS17 gene, which segregated with the phenotype in the pedigree. This variant site is in three TSP1 repeats, which may destabilize zonules by affecting ECM and microfibril assembly, causing zonular abnormalities, spherical crystals, or crystal subluxation.
Acknowledgments
Foundations: Supported by The Cadre Health Research Program of the Sichuan Province (No.2023-119); Sichuan Science and Technology Program (No.2021YFS0213).
Conflicts of Interest: Miao N, None; Zhang Y, None; Liao JY, None; Zhou L, None; He JC, None; Yang RQ, None; Liu XY, None; Tang L, None.
REFERENCES
- 1.Yi HA, Zha X, Zhu YC, Lv J, Hu SZ, Kong YB, Wu GJ, Yang YL, He YS. A novel nonsense mutation in ADAMTS17 caused autosomal recessive inheritance Weill-Marchesani syndrome from a Chinese family. J Hum Genet. 2019;64(7):681–687. doi: 10.1038/s10038-019-0608-2. [DOI] [PubMed] [Google Scholar]
- 2.Haji-Seyed-Javadi R, Jelodari-Mamaghani S, Paylakhi SH, Yazdani S, Nilforushan N, Fan JB, Klotzle B, Mahmoudi MJ, Ebrahimian MJ, Chelich N, Taghiabadi E, Kamyab K, Boileau C, Paisan-Ruiz C, Ronaghi M, Elahi E. LTBP2 mutations cause Weill–Marchesani and Weill–Marchesani-like syndrome and affect disruptions in the extracellular matrix. Hum Mutat. 2012;33(8):1182–1187. doi: 10.1002/humu.22105. [DOI] [PubMed] [Google Scholar]
- 3.Morales J, Al-Sharif L, Khalil DS, Shinwari JMA, Bavi P, Al-Mahrouqi RA, Al-Rajhi A, Alkuraya FS, Meyer BF, Al Tassan N. Homozygous mutations in ADAMTS10 and ADAMTS17 cause lenticular myopia, ectopia lentis, glaucoma, spherophakia, and short stature. Am J Hum Genet. 2009;85(5):558–568. doi: 10.1016/j.ajhg.2009.09.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Dagoneau N, Benoist-Lasselin C, Huber C, Faivre L, Mégarbané A, Alswaid A, Dollfus H, Alembik Y, Munnich A, Legeai-Mallet L, Cormier-Daire V. ADAMTS10 mutations in autosomal recessive Weill-marchesani syndrome. Am J Hum Genet. 2004;75(5):801–806. doi: 10.1086/425231. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Yang GY, Huang X, Chen BJ, Xu ZP. Weill-Marchesani-like syndrome caused by an FBN1 mutation with low-penetrance. Chin Med J. 2021;134(11):1359–1361. doi: 10.1097/CM9.0000000000001406. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Yu XW, Kline B, Han Y, Gao Y, Fan ZG, Shi Y. Weill-Marchesani syndrome 4 caused by compound heterozygosity of a maternal submicroscopic deletion and a paternal nonsense variant in the ADAMTS17 gene: a case report. Am J Ophthalmol Case Rep. 2022;26:101541. doi: 10.1016/j.ajoc.2022.101541. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Lin ZH, Zhu MJ, Deng HW. A pedigree report of a rare case of Weill-marchesani syndrome with new compound heterozygous LTBP2 mutations. Risk Manag Healthc Policy. 2021;14:1785–1789. doi: 10.2147/RMHP.S307290. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Newell K, Smith W, Ghoshhajra B, Isselbacher E, Lin A, Lindsay ME. Cervical artery dissection expands the cardiovascular phenotype in FBN1-related Weill–Marchesani syndrome. Am J Med Genet A. 2017;173(9):2551–2556. doi: 10.1002/ajmg.a.38353. [DOI] [PubMed] [Google Scholar]
- 9.Radner FPW, Marrakchi S, Kirchmeier P, Kim GJ, Ribierre F, Kamoun B, Abid L, Leipoldt M, Turki H, Schempp W, Heilig R, Lathrop M, Fischer J. Mutations in CERS3 cause autosomal recessive congenital ichthyosis in humans. PLoS Genet. 2013;9(6):e1003536. doi: 10.1371/journal.pgen.1003536. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Khan AO, Aldahmesh MA, Al-Ghadeer H, Mohamed JY, Alkuraya FS. Familial spherophakia with short stature caused by a novel homozygous ADAMTS17 mutation. Ophthalmic Genet. 2012;33(4):235–239. doi: 10.3109/13816810.2012.666708. [DOI] [PubMed] [Google Scholar]
- 11.Shah MH, Bhat V, Shetty JS, Kumar A. Whole exome sequencing identifies a novel splice-site mutation in ADAMTS17 in an Indian family with Weill-Marchesani syndrome. Mol Vis. 2014;20:790–796. [PMC free article] [PubMed] [Google Scholar]
- 12.Karoulias SZ, Beyens A, Balic Z, Symoens S, Vandersteen A, Rideout AL, Dickinson J, Callewaert B, Hubmacher D. A novel ADAMTS17 variant that causes Weill-Marchesani syndrome 4 alters fibrillin-1 and collagen type I deposition in the extracellular matrix. Matrix Biol. 2020;88:1–18. doi: 10.1016/j.matbio.2019.11.001. [DOI] [PubMed] [Google Scholar]
- 13.Mead TJ, Apte SS. ADAMTS proteins in human disorders. Matrix Biol. 2018;71-72:225–239. doi: 10.1016/j.matbio.2018.06.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Hubmacher D, Schneider M, Berardinelli SJ, Takeuchi H, Willard B, Reinhardt DP, Haltiwanger RS, Apte SS. Unusual life cycle and impact on microfibril assembly of ADAMTS17, a secreted metalloprotease mutated in genetic eye disease. Sci Rep. 2017;7:41871. doi: 10.1038/srep41871. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Oliver JAC, Rustidge S, Pettitt L, Jenkins CA, Farias FHG, Giuliano EA, Mellersh CS. Evaluation of ADAMTS17 in Chinese Shar-Pei with primary open-angle glaucoma, primary lens luxation, or both. Am J Vet Res. 2018;79(1):98–106. doi: 10.2460/ajvr.79.1.98. [DOI] [PubMed] [Google Scholar]
- 16.Jeanes EC, Oliver JAC, Ricketts SL, Gould DJ, Mellersh CS. Glaucoma-causing ADAMTS17 mutations are also reproducibly associated with height in two domestic dog breeds: selection for short stature may have contributed to increased prevalence of glaucoma. Canine Genet Epidemiol. 2019;6:5. doi: 10.1186/s40575-019-0071-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Lango Allen H, Estrada K, Lettre G, et al. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature. 2010;467(7317):832–838. doi: 10.1038/nature09410. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.van Duyvenvoorde HA, Lui JC, Kant SG, et al. Copy number variants in patients with short stature. Eur J Hum Genet. 2014;22(5):602–609. doi: 10.1038/ejhg.2013.203. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Oichi T, Taniguchi Y, Soma K, Oshima Y, Yano F, Mori Y, Chijimatsu R, Kim-Kaneyama JR, Tanaka S, Saito T. Adamts17 is involved in skeletogenesis through modulation of BMP-Smad1/5/8 pathway. Cell Mol Life Sci. 2019;76(23):4795–4809. doi: 10.1007/s00018-019-03188-0. [DOI] [PMC free article] [PubMed] [Google Scholar]