Introduction: Weill-Marchesani syndrome (WMS) is a hereditary connective tissue disorder with substantial heterogeneity in clinical features and genetic etiology, so it is essential to define the full mutation spectrum for earlier diagnosis. In this study, we report Weill-Marchesani-like syndrome (WMS-like) change to autosomal dominance inheritance caused by novel haplotypic mutations in latent transforming growth factor beta-binding protein 2 (LTBP2). Methods: Twenty-five members from a 4-generation Chinese family were recruited from Guangzhou, of whom nine were diagnosed with WMS-like disease, nine were healthy, and seven were of “uncertain” clinical status because of their young age. All members received detailed physical and ocular examinations. Whole-exome sequencing, Sanger sequencing, and real-time PCR were used to identify and verify the causative mutations in family members. Results: Genetic sequencing revealed novel haplotypic mutations on the same LTBP2 chromosome associated with WMS-like, c. 2657C>A/p.T886K in exon 16 and deletion of exons 25–36. Real-time PCR and Sanger sequencing verified both mutations in patients with clinically diagnosed WMS-like, and in one “uncertain” child. In these patients, the haplotypic mutations led to ectopia lentis, short stature, and obesity. Conclusion: Our study revealed that WMS-like may be associated with haplotypic LTBP2 mutations with autosomal dominant inheritance.

Weill-Marchesani syndrome (WMS) is a rare connective tissue disorder characterized by short stature (present in 90% of cases), brachydactyly with progressive joint stiffness, cardiovascular defects, and ocular abnormalities including microspherophakia, ectopia lentis, severe myopia, and glaucoma [1, 2]. Patients exhibiting only some of these WMS signs may be diagnosed with Weill-Marchesani-like syndrome (WMS-like) [3]. At present, there are no consensus clinical diagnostic criteria for WMS, and diagnosis may be delayed until clinical characteristics emerge in childhood or genetic testing identifies a known associated mutation.

Despite many common clinical features, there is genetic heterogeneity among WMS patients [1]. To date, a total of four pathogenic genes have been identified: ADAMTS10 and ADAMTS17 (encoding a disintegrin and metalloproteinase with thrombospondin motifs 10 and 17), LTBP2 (encoding latent transforming growth factor beta-binding protein 2), and FBN1 (encoding fibrillin-1), and inheritance may be either autosomal dominant (AD) or autosomal recessive (AR) [4‒7]. Usually, mutations in FBN1 are associated with AD inheritance, whereas biallelic pathogenic mutations in ADAMTS10, ADAMTS17, or LTBP2 cause the AR form. Recently, compound heterozygous variants (variations with two alleles at the same locus) in LTBP2 have been identified in patients with microspherophakia or WMS [8, 9]. However, there have been no reports of LTBP2 being associated with the AD form in families. In addition, copy number variants (CNVs) have never been reported in WMS patients.

The LTBP2 gene is located at 14q24.3 and has 36 exons [10] encoding the largest member of the LTBP family [11]. The protein product of LTBP2 is a member of the extracellular matrix (ECM) superfamily of structural proteins, also including three fibrillins and three additional LTBP proteins [12]. Mutations in the LTBP2 protein can affect the formation and stability of microfibril bundles [13] and alter the physiological activities of its binding target TGF-b, including TGF-b-induced expression of various other ECM components [14]. Functional LTBP2 is required for the assembly of microfibrils on ciliary epithelial cells and the formation of ciliary zonules, leading to ectopia lentis and secondary glaucoma [15]. In addition, the LTBP2 is also expressed in the trabecular meshwork, and mutation can result in congenital glaucoma [16].

In this study, we discovered novel haplotypic mutations (two variations at two loci on the same LTBP2 chromosome) were related to AD WMS-like in a Chinese family. According to our knowledge, this is the first report of a CNV in LTBP2 linked to WMS-like and WMS-like linked to LTBP2 mutations demonstrating the inheritance of AD.

Patients and Clinical Data

The participants were members of a four-generation family. The proband first visited Zhongshan Ophthalmic Center (ZOC) due to progressive blurred vision in his teens. The proband and remaining family members all received comprehensive family history reviews as well as systemic and ophthalmic examinations. Ophthalmic examinations included visual acuity, intraocular pressure, slit lamp, corneal refraction, axial length (A-ultrasound), fundus, and ocular B-ultrasound. Systemic examinations included height, weight, X-rays for bone structure, and echocardiography to assess cardiac function. This study was approved by the Ethics Reviewer Board of ZOC. The study was performed in accordance with the principles of the Declaration of Helsinki, and written informed consent was obtained from all participants and from the parent/legal guardian/next of kin of all participants aged under 18 years old.

Whole-Exome Sequencing and Mutation Identification

Whole-exome sequencing (WES) was conducted by Genokon Medical (Xiamen, China) to screen candidate pathogenic genes. Peripheral whole blood was collected from each participant, and genomic DNA was isolated using a TIANamp Blood DNA Kit (Tiangen Biotech, Beijing, China). Qualified genomic DNA was then randomly cut into fragments >150 bp. The fragment ends were repaired and ligated sequentially to A-tails and an indexing-specific adapter, followed by magnetic bead purification and PCR amplification. Following hybridization and another round of PCR amplification, the captured products were tested for quality using the Agilent 2100 Bioanalyzer. Finally, retained fragments were sequenced by DNBSEQ.

The raw data generated by the sequencer were filtered by removing low-quality reads, duplicate reads, and undetected base reads. Clean data were then aligned with the reference sequence of the human genome (GRCh37/hg19) using the Burrows-Wheeler Aligner software package. Single nucleotide variants (SNVs) and short insertions and deletions (Indels) were detected using Genome Analysis Toolkit (GATK) software and CNVs using CNVkit software. Variants with frequencies less than 0.005 according to the Genome Aggregation Database (gnomAD), Exome Aggregation Consortium (ExAC), and 1000 Genomes Project and potentially associated with WMS phenotypes were considered candidate pathological mutations. The pathological impact of identified SNVs was predicted using polymorphism PolyPhen2, MutationTaster, and Sorting Intolerant from Tolerant (SIFT). Mutations were considered novel if they were not reported in the ClinVar Database.

Real-Time PCR and Sanger Sequencing Verification

Identified SNVs and CNVs mutations were validated by Sanger sequencing and real-time PCR (RT-PCR), respectively. The candidate SNV mutation ultimately identified in LTBP2 was amplified by PCR using forward primer TGA​CCT​CCA​TCC​TGG​GTA​GG and reverse primer CTC​AAC​TCG​GCC​TCT​TAG​CC, and PCR products were then sequenced using an ABI 3730xl DNA Analyzer. The PCR sequence obtained was compared to the reference sequence on the NCBI website. The candidate CNV was confirmed by RT-PCR using an upstream primer pair for exon 26 (forward: ATA​TTG​ACG​AGT​GTG​AGG​AC, reverse: AGA​ACA​CAG​CGG​TAG​GAG) and a downstream primer pair for intron 35 (forward: AGG​CTG​GAA​GGG​AAG​AAA, reverse: CCA​AGC​AAC​TCA​AGG​ACA​A), which yielded PCR products of 80–200 bp. Note that the downstream primer was designed for intron 35 because exon 35 is too short to design specific primers. And it could be inferred that exon 35 was missing if the adjacent downstream intron 35 was missing. Genomic GAPDH was used as an endogenous control (forward primer: ACT​AGC​GGT​TTT​ACG​GGC​G, reverse primer: CGA​CGC​AAA​AGA​AGA​TGC​GG). Samples from RT-PCR were assayed using SYBR Green. Relative DNA content for each target sequence was calculated as relative quantification (RQ) = 2-ΔΔCt, where RQ = 0 indicates homozygous loss, 0.4 < RQ <0.7 indicates heterozygous loss, 0.7 < RQ <1.3 indicates no CNV, 1.3 < RQ <1.7 indicates heterozygous duplication, and 1.7 < RQ <2.2 indicates homozygous duplication. Finally, the verified mutations were confirmed as disease-related by co-segregation analysis in family members of the proband.

Clinical Manifestations of WMS-Like in the Proband and Affected Family Members

The detailed family pedigree is shown in Figure 1. The proband (III-5), a young male, was initially referred to ZOC with binocular progressive blurred vision in May 2005. At that time, the patient demonstrated low uncorrected visual acuity (OD: 0.1, OS: 0.1) and low best corrected visual acuity (OD: 0.2, OS: 0.7), while corneal refractive powers were normal (OD: 42.94 D, OS: 42.94 D). Axial lengths were 24.93 mm for OD and 25.05 mm for OS. Intraocular pressure was normal in both eyes (OD: 15.4 mm Hg, OS: 15.4 mm Hg). Slit-lamp examination confirmed normal bilateral conjunctiva, sclera, and cornea, and an anterior chamber depth of about 3 corneal thicknesses. After dilating the pupils, we found that bilateral lenses were subluxated subtemporally with elongated suspensory ligaments and obtuse lens equators. No microspherophakia sign was found by slit-lamp microscopy. The right fundus was not visible due to a mature cataract. The left fundus was unremarkable. Binocular B-ultrasound revealed no obvious abnormalities in either eye.

Fig. 1.

The family pedigree. The asterisks indicate eight family members who underwent WES sequencing. III-5 is the proband.

Fig. 1.

The family pedigree. The asterisks indicate eight family members who underwent WES sequencing. III-5 is the proband.

Close modal

The proband was 169 cm tall and 75 kg without brachydactyly or progressive joint stiffness. No positive signs were found by echocardiography. In 2005, “lensectomy combined with intraocular lens suspension” was conducted for “ectopia lentis” of the right eye, and then the same procedure was performed in the left eye due to “ectopia lentis” in 2012. After these two surgeries, visual acuity was 0.8 in the right eye and 0.6 in the left eye, and binocular fundus examinations revealed no abnormalities. In 2012, however, the proband received a left eye vitrectomy for “rhegmatogenous retinal detachment,” which resulted in secondary glaucoma. During the last presentation in 2016, the final visual acuity in the left eye was 0.03, while the visual acuity of the right eye was stable at 0.8.

Similar to the proband, the other affected family members developed symptoms at about 13 years old; all were of short stature and obesity (adult males were 160–169 cm in height and 70–85 kg in weight; adult females were 155–160 cm in height and 62–72 kg in weight) and showed different degrees of ectopia lentis. Correspondingly, non-affected adult males were 168–175 cm in height and 62–85 kg in weight; non-affected adult females were 155–163 cm in height and 44–60 kg in weight. At the time of our study, all affected members in the second and third generations had received “lensectomy combined with IOL suspension” and demonstrated good visual acuity, normal fundus appearances, and no signs of glaucoma. Members of the fourth generation (except IV-3, 12 years old in 2016) were too young to be evaluated for disease phenotype. However, long-term follow-up was recommended. Figure 2 shows the ectopia lentis of IV-3. The patient (IV-3)’s uncorrected visual acuity was 1.2 in the right eye with no refractive error. Left eye’s uncorrected visual acuity was 0.3 with −1.25 DS (spherical lens) and −0.50 DC (cylindrical lens)×35. The best corrected visual acuity of the left eye was 1.0.

Fig. 2.

a, b Slit-lamp photos and ultrasound biomicroscope (UBM) examination of IV-3 showing ectopia lentis.

Fig. 2.

a, b Slit-lamp photos and ultrasound biomicroscope (UBM) examination of IV-3 showing ectopia lentis.

Close modal

Detection of Mutations by WES and Confirmation by Sanger Sequencing

We performed WES on 5 patients (II-2, III-1, III-7, III-8, and III-12) and three healthy family members (II-1, III-6, III-11). Based on clinical ectopia lentis and short stature, we considered two mutations in chromosome 14 LTBP2 as candidates related to the phenotype: one SNV (missense mutation c.2657C>A in exon 16) and one CNV (deletion of exons 26–35). Both mutations originate from the same chromosome of the same ancestor (II-2). Next, Sanger sequencing (performed on 18 family members) confirmed that all 7 patients (II-2, II-3, III-1, III-7, III-8, III-12, IV-3) and one “uncertain” child (IV-7) had the heterozygous missense mutation c.2657C>A in exon 16(Fig. 3a).

Fig. 3.

Sanger sequencing results and amino acid conservation analysis of LTBP2 in our study. a Sanger sequencing analysis of LTBP2: c.2657C>A in 18 family members. The mutation site is indicated by the red arrow. b Amino acid sequence alignment of LTBP2 across five species. The p.T886K mutation (red box) is within a region of LTBP2 that is highly conserved across these species.

Fig. 3.

Sanger sequencing results and amino acid conservation analysis of LTBP2 in our study. a Sanger sequencing analysis of LTBP2: c.2657C>A in 18 family members. The mutation site is indicated by the red arrow. b Amino acid sequence alignment of LTBP2 across five species. The p.T886K mutation (red box) is within a region of LTBP2 that is highly conserved across these species.

Close modal

The c.2657C>A (p.T886K) mutation (resulting in replacement of threonine with lysine, T to K) was recorded in the ClinVar database as of “uncertain significance,” and there are no relevant disease literature reports. The genomic evolution rate profiling score of the c.C2657A mutation (2.88 > cutoff value 2) and comparisons with 4 other species (Pan troglodytes, Canis lupus familiaris, Bos taurus, and Rattus norvegicus) indicated that the encoded amino acid residue occurred in a highly conserved region, suggesting potential harm to humans (Fig. 3b). Furthermore, the mutation is predicted to be “probably damaging” by PolyPhen2 (score of 0.99, > cut-off value 0.95), “deleterious” by SIFT, and “polymorphism” by MutationTaster (prob: 0.83), suggesting that protein functions may be affected.

Confirmation of a CNV by RT-PCR

WES also detected the deletion of exons 26–35 not found in the ClinVar database. We performed RT-PCR tests in 3 patients (III-5, III-7, and III-12), two healthy adult family members (II-1, III-11), and five “uncertain” children (IV-1, IV-2, IV-4, IV-5, and IV-7) to confirm the CNV. As shown in Figure 4, the RQ of all patients was between 0.3 and 0.7, whereas that of healthy adult family members was 0.7–1.3. Among the five as yet “uncertain” children, IV-7 carried the CNV mutation while IV-1, IV-2, IV-4, and IV-5 did not, consistent with the results of Sanger sequencing.

Fig. 4.

The RT-PCR results confirmed deletion of LTBP2 exon 26 and intron 35 in 3 patients and one “uncertain” child.

Fig. 4.

The RT-PCR results confirmed deletion of LTBP2 exon 26 and intron 35 in 3 patients and one “uncertain” child.

Close modal

Sanger sequencing and RT-PCR showed that the CNV and SNV were harbored as haplotypic mutations on the same LTBP2 chromosome inherited from patient II-2 (the mother of the proband). As the two variants are located on the same chromosome, it is currently difficult to distinguish the genetic effects caused by a single mutation, especially the CNV.

As a connective tissue disorder, WMS may lead to abnormalities in a multitude of tissues and organs, including skeletal, cardiovascular, and ocular tissues. Patients not meeting the full clinical spectrum, such as individuals with short stature and ocular manifestations but without brachydactyly or progressive joint stiffness, may be diagnosed with WMS-like [3, 17]. To date, pathogenic mutations associated with WMS or WMS-like have been found in ADAMTS10, ADAMTS17, LTBP2, and FBN1 [18]. Thus, the diagnosis can be established in patients with inconclusive clinical features by the identification of pathogenic gene variants. In our study, the co-occurrence of short stature and ectopia lentis along with LTBP2 mutations supported the diagnosis of WMS-like.

Microfibrils are obligatory components of the ECM, serving as scaffolds for elastin deposition in elastic fibers and forming thick bundles for tissue compartmentalization, such as in ciliary zonules [19]. Microfibrils are composed of fibrillins, LTBPs, and other associated glycoproteins. LTBP2 is highly expressed in the trabecular meshwork, ciliary bodies, lens capsule/lens epithelium layer [20], and other elastic connective tissues, such as the lungs and arteries [21]. Interestingly, although this specific expression pattern occurs in multiple tissues, disease phenotypes associated with LTBP2 mutations primarily present with ocular abnormalities, including ectopia lentis, microspherophakia, and congenital or secondary glaucoma. Compensatory overexpression of LTBP4 may explain why systemic connective tissue abnormalities are infrequent [13]. LTBP2 and LTBP4 have overlapping functions in the establishment of stable microfibrils in the lungs and eyes in vivo. However, due to the low expression of LTBP4 in ciliary bodies, LTBP2 mutations may be sufficient to cause the ocular phenotype.

Our findings expand the LTPB2 mutation spectrum and point to a novel mode of inheritance for LTBP2-associated WMS-like. Prior to this, all LTBP2 mutations associated with WMS had been reported as SNVs, which showed that either homozygous or compound heterozygous mutations induced WMS or WMS-like and were inherited in an AR manner [6, 9]. But now, we have discovered a CNV combined with an SNV that is inherited in AD mode in LTBP2. The LTBP2-haplotypic mutations co-segregated with WMS-like. The missense mutation at C2657 had an extremely low frequency (frequency <0.005) in the gnomAD, ExAC, and 1000 Genomes Project databases, and currently there was no population mutation frequency data for the CNV. Moreover, the c.2657C>A/mutation occurred within a highly conserved region, and both PolyPhen2 and SIFT predicted the mutation as “deleterious.” No CNV mutation data were found in the DECIPHER and ClinVar database. LTBP2 had 36 exons. Our RT-PCR results revealed lower gene expression level of LTBP2 exon 26 and intron 35. Deleting 26–35 exons might significantly alter the function of the LTBP2 protein, as the removal of large exons could influence the protein’s production and structure. In this case, the CNV mutation leading to a pathological phenotype may be due to haploinsufficiency, that is, an individual has only a single functional copy of a gene, and the single functional copy of the gene does not produce enough protein production. However, on the same LTBP2 chromosome, all patients in our study had two mutations: SNV and CNV at two luci. So, it is unclear whether the occurrence of WMS-like and the change in inheritance mode to AD were caused by the CNV alone or by a synergy between mutations.

For AR inheritance, the pathogenic genes must be homozygous or compound heterozygous at the same locus. We hypothesize that CNV-induced protein loss is the primary driver of disease onset and AD inheritance. The evidence presented below implies that CNV is to blame for the altered genomic pattern seen in our study. In 2012, Haji-Seyed-Javadi et al. [6] reported a heterozygous c.1642C>T (p.Arg548∗) mutation in exon 7 of LTBP2 in a patient with Marfan syndrome exhibiting primary glaucoma, mitral valve prolapse, and pectus excavatum. In this case, the introduction of a premature stop codon resulted in the extensive loss of the LTBP2 protein. Compared to the mutations described by Haji-Seyed-Javadi R, patients with WMS-like in our study had a CNV (deletion of exons 26–35), which directly led to the loss of the relevant region of the LTBP2 protein and was sufficient to cause disorder in patients. As a result, those who inherited this chromosome may develop disease, showing an AD mode of inheritance. The reason for the milder disease phenotype in our patients (presenting mainly with short stature and ectopia lentis but without abnormalities in joint, pulmonary, and cardiovascular systems) was the smaller extent of LTBP2 protein loss. Therefore, we hypothesize that the pathogenesis of this family and the shift in inheritance mode in our study are mainly due to haploid deficiency from the CNV (deletion of exons 26–35), while the SNV (c. 2657C>A/p.T886K) plays a secondary role.

There are several limitations to this study. First, additional structural and functional studies are needed to assess the effects of these two mutations on protein expression and function, as well as on changes in connective tissue properties. Second, preoperative slit-lamp photography of the proband (III-5) could not be found, so analysis was restricted to slit-lamp photographs and UBM of the offspring (IV-3). Third, we did not use Sanger and RT-PCR to verify the two mutations in all family members due to a lack of blood samples. Furthermore, methods such as long-range PCR and multiplex ligation-dependent probe amplification are a better choice for the CNV verification if possible. Finally, because of the late onset of the disease, further observation and follow-up are necessary to verify WMS-like manifestations in the fourth generation family members, especially IV-7, harboring the LTBP2 haplotypic mutation.

In conclusion, we report novel haplotypic mutations in LTBP2, c. 2657C>A/p.T886K in exon 16, and deletion of exons 25–36, associated with AD WMS-like in a Chinese family. Our study expands the LTPB2 mutation spectrum and potential inheritance modes of WMS.

The authors thank all the participants of the present study for their contribution.

The study was approved by the Ethics Committee of the Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, Guangdong (approval number: 2019KYPJ183). And the research was performed in accordance with the principles of the Declaration of Helsinki, and written informed consent was obtained from all participants and from the parent/legal guardian/next of kin of all participants aged under 18 years old.

None of the authors have any proprietary interests or conflicts of interest related to this submission.

This study was supported by the National Natural Science Foundation of China (82101118, 81873673 and 81900841) and the Five-five Clinical Specialty Construction Project (3030901010068).

Liuxueying Zhong contributed to the conception, design of the work, data acquisition, manuscript editing, and manuscript review. Juan Chen and Jifeng Wan contributed to literature search, clinical studies, experimental studies, statistical analysis, and manuscript preparation; Jiayi Jin and Guangming Jin contributed to data analysis and statistical analysis; and Yongxin Zheng and Danying Zheng contributed to data acquisition, data analysis, and manuscript review.

Additional Information

Juan Chen and Jifeng Wan contributed equally to this work and should be considered co-first authors.

The data that support the findings of this study are not publicly available due to privacy reasons but are available from the corresponding author upon reasonable request.

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