Abstract

Proximal symphalangism (SYM1) is an autosomal dominant disorder manifested by ankylosis of the proximal interphalangeal joints of fingers, carpal and tarsal bone fusion, and conductive hearing loss in some cases. Herein, we clinically diagnosed a Chinese patient with fusions of the bilateral proximal interphalangeal joints in the 2–5 digits without conductive hearing loss. Family history investigation revealed that his mother and grandfather also suffered from SYM1. Whole exome sequencing was performed to detect the genetic lesion of the family. The candidate gene variants were validated by Sanger sequencing. By data filtering, co-segregation analysis and bioinformatics analysis, we highly suspected that an unknown heterozygous frameshift variant (c.635_636insG, p.Q213Pfs*57) in NOG was responsible for the SYM1 in the family. This variant was predicted to be deleterious and resulted in a prolonged protein. This finding broadened the spectrum of NOG mutations associated with SYM1 and contributed to genetic diagnosis and counseling of families with SYM1.

Introduction

Proximal symphalangism (SYM1) is a hereditary disorder manifested by ankylosis of the proximal interphalangeal joints, carpal and tarsal bone fusion, and conductive hearing loss in some cases [1]. The typical features of SYM1 are reduced proximal interphalangeal joint space, symphalangism of the 4th and/or 5th finger [2,3]. The estimated prevalence of SYM1 is less than 1/1000000 with autosomal dominant inherited pattern [4,5]. And the first family with ankylosis of the proximal interphalangeal joints was reported and named as symphalangism in 1916 [6].

At present, at least two types of SYM1 have been identified in the clinic. One is proximal symphalangism-1A (SYM1A; OMIM 185800), which was caused by genetic variants in NOG (noggin), another is proximal symphalangism-1B (SYM1B; OMIM 615298), which resulted from GDF5 (growth differentiation factor 5) mutations [2,7]. However, due to the extensive pleiotropy, several other diseases may be also related to NOG, such as tarsal-carpal coalition syndrome, multiple synostoses syndrome, and brachydactyly, etc. [8]. Hence, detection the genetic lesion of the patients with SYM1 may further confirm the clinical diagnosis and help us to understand the development of bone.

In the present study, we enrolled a family with SYM1 from central south region of China. The aim of the present study was to detect the genetic lesion of the affected individuals by employing whole exome sequencing and bioinformatics analysis.

Materials and methods

Subjects and ethical approval

The proband (Figure 1A, III:2) was a 6-year-old boy from a non-consanguineous Chinese family. According to the family history investigation, mother (II:4) and grandfather (I:1) of proband also had the phenotype of limited fingers bilaterally, they may be patients with SYM1. We found the fourth to fifth fingers bilaterally of his mother were limited after preliminary diagnosis. Unfortunately, the proband’s mother refused further diagnosis and treatment and grandfather has already passed away. The photographs showed the second to fifth fingers and toes bilaterally of the proband were limited and cannot make a fist (Figure 1B). The radiographs indicated the reduced proximal interphalangeal joint space and further confirmed the clinical diagnosis (Figure 1C). No other significant phenotypes were found, such as hearing loss.

The clinical data of the family with SYM1

Figure 1
The clinical data of the family with SYM1

(A) The pedigree of this family. Black circles/squares are affected, white circles/squares are unaffected. Arrow indicates the proband. The question mark indicates that the illness is uncertain. (B) The proband showed the symphalangism of second to fifth fingers. (C) Hands X-ray of III-2. The red circles and arrows marked the abnormal regions.

Figure 1
The clinical data of the family with SYM1

(A) The pedigree of this family. Black circles/squares are affected, white circles/squares are unaffected. Arrow indicates the proband. The question mark indicates that the illness is uncertain. (B) The proband showed the symphalangism of second to fifth fingers. (C) Hands X-ray of III-2. The red circles and arrows marked the abnormal regions.

The Review Board of the Xiangya Hospital of the Central South University approved the present study. Given the proband is too young, written consent forms were signed by his parents as guardians.

Genetic analysis

Genomic DNA was prepared from peripheral blood of the patients and other all participants using a DNeasy Blood &Tissue Kit (Qiagen, Valencia, CA, U.S.A.). Genomic DNA was extracted from the peripheral blood lymphocytes of all family members by using a DNeasy Blood & Tissue Kit (Qiagen, Valencia, CA, U.S.A.) following the manufacturer’s instruction. The central part of the whole exome sequencing was provided by the Novogene Bioinformatics Institute (Beijing, China). The exomes were captured using Agilent SureSelect Human All Exon V6 kits, and high-throughput sequencing was performed using Illumina HiSeq X-10. The necessary bioinformatics analyses, including reads, mapping, variant detection, filtering, and annotation, were also endowed by Novogene Bioinformatics Institute [9].

The strategies of data filtering refer to our previous study [9]: (a) variants within intergenic, intronic, and UTR regions as well as synonymous mutations were excluded for later analysis; (b) variants with MAF>0.01 in the 1000 Genomes project, dbSNP132 were excluded; (c) variants with MAF>0.01 in genome aggregation database (gnomAD) (http://gnomad.broadinstitute.org/) were further precluded; (d) SIFT, Polyphen-2 and MutationTaster were utilized to predict the possible impacts of variants. (e) Co-segregation analysis was conducted in the family.

Result

The WES raw data had a mean depth of 125.66 on target, target region coverage of 98.05%, target region coverage (at least 10×) of 97.27%, indicating the high sequencing quality. After data filtering, only 16 variants were included in Table 1. We then further performed bioinformatic analysis including Inheritance pattern and OMIM clinical phenotypes analysis (https://www.omim.org/), ToppGene gene function analysis (https://toppgene.cchmc.org/) and The American College of Medical Genetics and Genomics (ACMG) classification, we highly suspected the unknown variant (NM_005450, c.635_636insG, p.Q213Pfs*57) of NOG, belonging to PM1, PM2, PM4, PP1, PP3, and PP4 (likely pathogenic) in ACMG guidelines [10], was the genetic lesion of the family (Figure 2A). The result of co-segregation analysis showed the same unknown variant exist in mother of proband but not in his father. The unknown variant, which led to alteration of amino acid residues after position 212 and a prolonged protein (Figure 2B), was predicted as “Disease Causing” (0.99) by MutationTaster (http://www.mutationtaster.org/) and not found on the 1000 Genome Browser, the gnomAD Browser and the Exome Variant Server, and was not presented in 200 control cohorts. Multiple alignment of noggin orthologs in other animal species showed that amino acid sequence after position 212 was highly conserved (Figure 2C).

The genetic analysis of the variant

Figure 2
The genetic analysis of the variant

(A) Sanger DNA sequencing chromatogram demonstrates the heterozygosity for a NOG variant (c.635_636insG, p.Q213Pfs*57). (B) Rope diagram of noggin–BMP7 complex (SMTL ID: 1m4u.1), the upper and lower parts are noggin dimer and BMP7 dimer, respectively. The arrows and words indicate the Q213 site, the red amino acids rope after Q213 was affected in the patient. (C) Alignment of the amino acid sequences of noggin. The affected amino acids locate in the highly conserved amino acid region in different species (from Ensembl). The arrow and words show the Q213 site.

Figure 2
The genetic analysis of the variant

(A) Sanger DNA sequencing chromatogram demonstrates the heterozygosity for a NOG variant (c.635_636insG, p.Q213Pfs*57). (B) Rope diagram of noggin–BMP7 complex (SMTL ID: 1m4u.1), the upper and lower parts are noggin dimer and BMP7 dimer, respectively. The arrows and words indicate the Q213 site, the red amino acids rope after Q213 was affected in the patient. (C) Alignment of the amino acid sequences of noggin. The affected amino acids locate in the highly conserved amino acid region in different species (from Ensembl). The arrow and words show the Q213 site.

Table 1
The gene list after data filtering in the family with SYM1
ChrPosRBABGeneMutationOMIMAllele frequencyTopp geneACMG
220275877 IARS2 NM_018060; c.C790T: p.H264Y AR: growth hormone deficiency Unknown variant Isoleucyl-tRNA aminoacylation PM2, BP6 Uncertain significance 
196681652 DNAH7 NM_018897; c.T9461C:p.V3154A Unknown variant Inner dynein arm assembly PM2, PP1, PP3 Uncertain significance 
233388655 PRSS56 NM_001195129; c.G1186A: p.E396K AR: microphthalmia Unknown variant Serine-type endopeptidase activity PM2, BP6 Uncertain significance 
118485627 DMXL1 NM_001290321; c.C4105T:p.R1369C – Unknown variant Vacuolar acidification PM2, PP1, PP3 Uncertain significance 
99116733 HRSP12 NM_005836; c.T335C: p.V112A – Unknown variant – PM2, PP1, PP3 Uncertain significance 
119461126 TRIM32 NM_001099679; c.G1105A: p.G369R AR: Bardet–Biedl syndrome Unknown variant Tat protein binding PM2, BP6 Uncertain significance 
12 992601 WNK1 NM_014823; c.T2789G: p.F930C AR: neuropathy; AD: pseudohypoaldosteronism Unknown variant  PM1, PM2 Uncertain significance 
12 49522372 TUBA1B NM_006082; c.T725G: p.L242R Unknown variant Chloride channel inhibitor activity PM2, PP1, PP3 Uncertain significance 
17 54672219 GG NOG NM_005450: c.635_636insG: p. Q213PfsX57 AD: symphalangism Unknown variant Fibroblast growth factor receptor signaling pathway PM1, PM2, PM4, PP1, PP3, PP4 Likely pathogenic 
17 71420107 SDK2 NM_001144952; c.C1708T: p.R570W – Unknown variant Camera-type eye photoreceptor cell differentiation PM2, PP1, PP3 Uncertain significance 
18 13071096 CEP192 NM_032142; c.G5233A: p.E1745K – Unknown variant Phosphatase binding PM2, PP1, PP3 Uncertain significance 
19 39321974 ECH1 NM_001398; c.A235C: p.N79H – Unknown variant Δ3,5-Δ2,4-Dienoyl-CoA isomerase activity PM2, PP1, PP3 Uncertain significance 
19 56128115 ZNF865 NM_001195605; c.T3131C: p.L1044P – Unknown variant – PM2, PP1, PP3 Uncertain significance 
20 25457050 CA NINL NM_025176; c.2876_2877insT: p.E959Dfs15 – Unknown variant Calcium ion binding PM2, PP1, PP3 Uncertain significance 
20 30785333 PLAGL2 NM_002657; c.C413T: p.T138M – Unknown variant Chylomicron assembly PM2, PP1, PP3 Uncertain significance 
131188838 STK26 NM_001042452; c.G222T:p.L74F – Unknown variant Microvillus assembly PM2, PP1, PP3 Uncertain significance 
ChrPosRBABGeneMutationOMIMAllele frequencyTopp geneACMG
220275877 IARS2 NM_018060; c.C790T: p.H264Y AR: growth hormone deficiency Unknown variant Isoleucyl-tRNA aminoacylation PM2, BP6 Uncertain significance 
196681652 DNAH7 NM_018897; c.T9461C:p.V3154A Unknown variant Inner dynein arm assembly PM2, PP1, PP3 Uncertain significance 
233388655 PRSS56 NM_001195129; c.G1186A: p.E396K AR: microphthalmia Unknown variant Serine-type endopeptidase activity PM2, BP6 Uncertain significance 
118485627 DMXL1 NM_001290321; c.C4105T:p.R1369C – Unknown variant Vacuolar acidification PM2, PP1, PP3 Uncertain significance 
99116733 HRSP12 NM_005836; c.T335C: p.V112A – Unknown variant – PM2, PP1, PP3 Uncertain significance 
119461126 TRIM32 NM_001099679; c.G1105A: p.G369R AR: Bardet–Biedl syndrome Unknown variant Tat protein binding PM2, BP6 Uncertain significance 
12 992601 WNK1 NM_014823; c.T2789G: p.F930C AR: neuropathy; AD: pseudohypoaldosteronism Unknown variant  PM1, PM2 Uncertain significance 
12 49522372 TUBA1B NM_006082; c.T725G: p.L242R Unknown variant Chloride channel inhibitor activity PM2, PP1, PP3 Uncertain significance 
17 54672219 GG NOG NM_005450: c.635_636insG: p. Q213PfsX57 AD: symphalangism Unknown variant Fibroblast growth factor receptor signaling pathway PM1, PM2, PM4, PP1, PP3, PP4 Likely pathogenic 
17 71420107 SDK2 NM_001144952; c.C1708T: p.R570W – Unknown variant Camera-type eye photoreceptor cell differentiation PM2, PP1, PP3 Uncertain significance 
18 13071096 CEP192 NM_032142; c.G5233A: p.E1745K – Unknown variant Phosphatase binding PM2, PP1, PP3 Uncertain significance 
19 39321974 ECH1 NM_001398; c.A235C: p.N79H – Unknown variant Δ3,5-Δ2,4-Dienoyl-CoA isomerase activity PM2, PP1, PP3 Uncertain significance 
19 56128115 ZNF865 NM_001195605; c.T3131C: p.L1044P – Unknown variant – PM2, PP1, PP3 Uncertain significance 
20 25457050 CA NINL NM_025176; c.2876_2877insT: p.E959Dfs15 – Unknown variant Calcium ion binding PM2, PP1, PP3 Uncertain significance 
20 30785333 PLAGL2 NM_002657; c.C413T: p.T138M – Unknown variant Chylomicron assembly PM2, PP1, PP3 Uncertain significance 
131188838 STK26 NM_001042452; c.G222T:p.L74F – Unknown variant Microvillus assembly PM2, PP1, PP3 Uncertain significance 

CHR, chromosome; POS, position; RB, reference sequence base; AB, alternative base identified; AR, autosomal recessive; AD, autosomal dominant; BP, benign supporting; PP, pathogenicity supporting; PM, pathogenicity moderate; PVS, pathogenicity very strong. The data of allele frequency were obtained from 1000G, ESP, and ExAC databases.

Discussion

In the present study, we enrolled a family with SYM1 from China. By employing whole exome sequencing, we identified an unknown frameshift variant (c.635_636insG, p.Q213Pfs*57) in the affected members. The variant resulted in the extension of noggin protein which may affect the function of the protein. Bioinformatics analysis further predicted this variant as disease-causing variant. Our study is consistent with previous studies which indicated that variants in NOG gene may lead to SYM1 and other bone diseases [11].

The human NOG gene encoding noggin protein is located on chromosome 17q22, and it consists of one exon, spanning approximately 1.9 kilobases (kb). Noggin, the first identified BMP antagonist, is posttranslationally modified and secreted as a disulfide-bonded homodimer. BMPs play essential roles in skeletogenesis including recruiting mesenchymal cells, promoting mesenchymal cell proliferation and differentiation into chondroblasts and osteoblasts, and inducing apoptosis to form joints [12–14]. Noggin can bind to BMPs and inhibit the interactions of BMPs and BMP-specific recptors, and therefore negatively regulates BMP-induces osteogenesis [15,16]. In the present study, the unknown variant was not located at the interface between the two molecules in noggin–BMP7 complex (SWISS-MODEL Template Library, ID: 1m4u.1), and no templates of sufficient quality to build a homology model were found for the changed sequence (Figure 2B). Whereas, according to the complex model and the prolonged sequence, we suspected the variant presumably affected the binding of noggin homodimer and further disrupt the structure of noggin–BMP7 complex, which actived the BMP signal pathway and lead to bone diseases. Further research is needed to confirm this hypothesis.

On the basis of reported papers, multiple bone diseases are associated with NOG mutations [17]. For example, at present, over 50 mutations of NOG involved in wide variety of bone development anomalies, including tarsal/carpal coalition syndrome, brachydactyly, multiple synostoses syndrome, stapes ankylosis with broad thumbs and toes, have been reported [5,18]. Even the same variants of NOG can lead to different phenotypes between different families or different affected members of the same family, see Table 2 [19,20]. Meanwhile, the variant was the sixth unknown variant reported in Chinese population, which indicated there were still a lot of unknown variants to be discovered in Chinese population. Here, we summarized the reported NOG mutations in Table 2, which may make us to understand the function of noggin better.

Table 2
The summary of reported mutations in NOG
No.MutationPhenotypesPMID
c. 58delC p. Leu20fs SYNS1 Hearing loss – 11846737 
c. 103C>G p. Pro35Ala BDB – – 17668388 
c. 103C>T p. Pro35Ser TCC Hearing loss Hyperopia 18440889 
c. 103C>T p. Pro35Ser SYM1 Hearing loss – 11857750 
c. 103C>T p. Pro35Ser BDB – – 17668388 
c. 104C>G p. Pro35Arg SYM1 – – 10080184 
c. 104C>G p. Pro35Arg TCC – – 11545688 
c. 106G>C p. Ala36Pro BDB – – 17668388 
c. 110C>G p. Pro37Arg TCC Hearing loss – 15264296 
10 c. 124C>G;
c. 149C>G 
p. Pro42Ala;
p. Pro50Arg 
TCC Hearing loss – 15736221 
11 c. 124C>T p. Pro42Ser SYM1 – – 31370824 
12 c. 125C>G p. Pro42Arg SYNS1 – – 18204269 
13 c. 124C>A p. Pro42Thr SYNS1 – – 23732071 
14 c. 125C>T p. Pro42Leu SYNS1 Hearing loss – 25241334 
15 c.130_131insGG p. Val44fs TCS Hearing loss Hyperopia 15699718 
16 c. 137T>C p. Leu46Pro SYM1 – – 22855651 
17 c. 142G>A p. Glu48Lys BDB – – 17668388 
18 c. 142G>A p. Glu48Lys POF and SYM1 Hearing loss – 15066478 
19 c. 163G>T p. Asp55Tyr SYM1 – – 31105738 
20 c. 252_253insG p. Glu85fs SABTT Hearing loss Hyperopia 12089654 
21 c. 261_262insG p. Pro88fs SYNS1 Hearing loss Hyperopia 25241334 
22 c. 271G>T p. Gly91Cys FOP – – 11503156 
23 c. 274G>C p. Gly92Arg FOP – – 11503156 
24 c. 275G>A p. Gly92Glu FOP – – 11503156 
25 c. 283G>A p. Ala95Thr FOP – – 16080294 
26 c. 304delG p. Ala102fs SYM1 Hearing loss Hyperopia 21358557 
27 c. 328C>T p. Gln110X SABTT Hearing loss Hyperopia 12089654 
28 c. 386T>A p. Leu129X SYM1 Hearing loss – 11846737 
29 c. 391C>T p.Gln131X SABTT Hearing loss Hyperopia 21358557 
30 c. 397A>T p. Lys133X SABTT Hearing loss Hyperopia 27508084 
31 c. 406C>T p. Arg136Cys SYM1 Hearing loss – 24735539 
32 c. 450G>C p. Trp150Cys SYM1 Hearing loss – 25888563 
33 c. 452C>A p. Ser151X SYNS1 Hearing loss – 25241334 
34 c. 463T>A p. Cys155Ser SYM1 Hearing loss – 22288654 
35 c. 499C>G p. Arg167Gly BDB – – 17668388 
36 c. 499C>T p. Arg167Cys SYM1 – – 24326127 
37 c. 551G>A p. Cys184Tyr SYM1 – – 11846737 
38 c. 551G>T p. Cys184Phe SYM1 Hearing loss Hyperopia 22288654 
39 c. 559C>T p. Pro187Ser BDB – – 17668388 
40 c. 559C>G p. Pro187Ala SYM1 Hearing loss – 25391606 
41 c. 561delC p. Pro187fs TCS Hearing loss Hyperopia 15699718 
42 c. 565G>T p. Gly189Cys SYM1 – – 10080184 
43 c. 568A>G p. Met190Val SYNS1 Hearing loss – 18204269 
44 c. 608T>C p. Leu203Pro TCS Hearing loss Hyperopia 15699718 
45 c. 611G>T p. Arg204Leu TCC – – 11545688 
46 c. 611G>G p. Arg204Gln TCC – – 29159868 
47 c. 614G>A p. Trp205X SYNS1 – – 16532400 
48 c. 615G>C p. Trp205Cys Facioaudiosymphalangism syndrome Hearing loss Hyperopia 15770128 
49 c. 615G>C p. Trp205Cys SABTT Hearing loss Hyperopia 19471170 
50 c. c.635_636insG p.Q213PfsX57 SYM1 – – Present study 
51 c. 645C>A p. Cys215X SABTT Hearing loss Hyperopia 22288654 
52 c. 649T>G p. Trp217Gly SYNS1 – – 10080184 
53 c. 659T>A p. Ile220Asn SYM1 – – 10080184 
54 c. 659_660delinsAT p. Ile220Asn SYM1 – – 10080184 
55 c. 664T>G p. Tyr222Asp SYM1 – – 10080184 
56 c. 665A>G p. Tyr222Cys SYM1 – – 10080184 
57 c. 665A>G p. Tyr222Cys TCC – – 11545688 
58 c. 668C>T p. Pro223Leu SYM1 – – 10080184 
59 c. 682T>G p. Cys228Gly SABTT Hearing loss Hyperopia 26211601 
60 c. 682T>A p. Cys228Ala SYNS1 Hearing loss Hyperopia 25391606 
61 c. 689G>A p. Cys230Tyr SYNS1 – Hyperopia 26994744 
62 c. 690C>G p. Cys230Trp SYM1 Hearing loss – 31694554 
63 c. 696C>G p. Cys232Trp SYNS1 Hearing loss Hyperopia 20503332 
No.MutationPhenotypesPMID
c. 58delC p. Leu20fs SYNS1 Hearing loss – 11846737 
c. 103C>G p. Pro35Ala BDB – – 17668388 
c. 103C>T p. Pro35Ser TCC Hearing loss Hyperopia 18440889 
c. 103C>T p. Pro35Ser SYM1 Hearing loss – 11857750 
c. 103C>T p. Pro35Ser BDB – – 17668388 
c. 104C>G p. Pro35Arg SYM1 – – 10080184 
c. 104C>G p. Pro35Arg TCC – – 11545688 
c. 106G>C p. Ala36Pro BDB – – 17668388 
c. 110C>G p. Pro37Arg TCC Hearing loss – 15264296 
10 c. 124C>G;
c. 149C>G 
p. Pro42Ala;
p. Pro50Arg 
TCC Hearing loss – 15736221 
11 c. 124C>T p. Pro42Ser SYM1 – – 31370824 
12 c. 125C>G p. Pro42Arg SYNS1 – – 18204269 
13 c. 124C>A p. Pro42Thr SYNS1 – – 23732071 
14 c. 125C>T p. Pro42Leu SYNS1 Hearing loss – 25241334 
15 c.130_131insGG p. Val44fs TCS Hearing loss Hyperopia 15699718 
16 c. 137T>C p. Leu46Pro SYM1 – – 22855651 
17 c. 142G>A p. Glu48Lys BDB – – 17668388 
18 c. 142G>A p. Glu48Lys POF and SYM1 Hearing loss – 15066478 
19 c. 163G>T p. Asp55Tyr SYM1 – – 31105738 
20 c. 252_253insG p. Glu85fs SABTT Hearing loss Hyperopia 12089654 
21 c. 261_262insG p. Pro88fs SYNS1 Hearing loss Hyperopia 25241334 
22 c. 271G>T p. Gly91Cys FOP – – 11503156 
23 c. 274G>C p. Gly92Arg FOP – – 11503156 
24 c. 275G>A p. Gly92Glu FOP – – 11503156 
25 c. 283G>A p. Ala95Thr FOP – – 16080294 
26 c. 304delG p. Ala102fs SYM1 Hearing loss Hyperopia 21358557 
27 c. 328C>T p. Gln110X SABTT Hearing loss Hyperopia 12089654 
28 c. 386T>A p. Leu129X SYM1 Hearing loss – 11846737 
29 c. 391C>T p.Gln131X SABTT Hearing loss Hyperopia 21358557 
30 c. 397A>T p. Lys133X SABTT Hearing loss Hyperopia 27508084 
31 c. 406C>T p. Arg136Cys SYM1 Hearing loss – 24735539 
32 c. 450G>C p. Trp150Cys SYM1 Hearing loss – 25888563 
33 c. 452C>A p. Ser151X SYNS1 Hearing loss – 25241334 
34 c. 463T>A p. Cys155Ser SYM1 Hearing loss – 22288654 
35 c. 499C>G p. Arg167Gly BDB – – 17668388 
36 c. 499C>T p. Arg167Cys SYM1 – – 24326127 
37 c. 551G>A p. Cys184Tyr SYM1 – – 11846737 
38 c. 551G>T p. Cys184Phe SYM1 Hearing loss Hyperopia 22288654 
39 c. 559C>T p. Pro187Ser BDB – – 17668388 
40 c. 559C>G p. Pro187Ala SYM1 Hearing loss – 25391606 
41 c. 561delC p. Pro187fs TCS Hearing loss Hyperopia 15699718 
42 c. 565G>T p. Gly189Cys SYM1 – – 10080184 
43 c. 568A>G p. Met190Val SYNS1 Hearing loss – 18204269 
44 c. 608T>C p. Leu203Pro TCS Hearing loss Hyperopia 15699718 
45 c. 611G>T p. Arg204Leu TCC – – 11545688 
46 c. 611G>G p. Arg204Gln TCC – – 29159868 
47 c. 614G>A p. Trp205X SYNS1 – – 16532400 
48 c. 615G>C p. Trp205Cys Facioaudiosymphalangism syndrome Hearing loss Hyperopia 15770128 
49 c. 615G>C p. Trp205Cys SABTT Hearing loss Hyperopia 19471170 
50 c. c.635_636insG p.Q213PfsX57 SYM1 – – Present study 
51 c. 645C>A p. Cys215X SABTT Hearing loss Hyperopia 22288654 
52 c. 649T>G p. Trp217Gly SYNS1 – – 10080184 
53 c. 659T>A p. Ile220Asn SYM1 – – 10080184 
54 c. 659_660delinsAT p. Ile220Asn SYM1 – – 10080184 
55 c. 664T>G p. Tyr222Asp SYM1 – – 10080184 
56 c. 665A>G p. Tyr222Cys SYM1 – – 10080184 
57 c. 665A>G p. Tyr222Cys TCC – – 11545688 
58 c. 668C>T p. Pro223Leu SYM1 – – 10080184 
59 c. 682T>G p. Cys228Gly SABTT Hearing loss Hyperopia 26211601 
60 c. 682T>A p. Cys228Ala SYNS1 Hearing loss Hyperopia 25391606 
61 c. 689G>A p. Cys230Tyr SYNS1 – Hyperopia 26994744 
62 c. 690C>G p. Cys230Trp SYM1 Hearing loss – 31694554 
63 c. 696C>G p. Cys232Trp SYNS1 Hearing loss Hyperopia 20503332 

SYNS1, multiple synostosis syndrome; BDB, brachydactyly type B; TCC, Trasal–Carpal coalition syndrome; SYM1, proximal symphalangism; TCS, Teunissen–Cremers syndrome; POF, premature ovarian failure; SABTT, stapes ankylosis with broad thumbs and toes; FOP, fibrodysplasia ossificans progressiva.

In additional to major bone diseases, patients with NOG mutations are often accompanied by other phenotypes, such as conductive hearing loss and hyperopia. In Table 2, we can find that these phenotypes are not always present in the same mutations or in different mutations at the same sites. Besides, in some papers, hearing loss do not exist in all affected members of same families [5,18]. These results seem to indicate that conductive hearing loss and hyperopia may appear randomly in patients with NOG mutations; whereas, in contrast with most NOG mutations that have been reported in kindreds with SYM1 and SYNS1, the mutations observed in families with stapes ankylosis without SYM1 are predicted to disrupt the cysteine-rich C-terminal domain [21,22]. In short, the relationship between NOG and these phenotypes is still unclear, further research is needed to understand that. Some patients with NOG mutations can also have nasal bone, elbow, shoulder, and spine anomalies except for hands and feet [11,14], suggested noggin protein plays an essential and extensive role in bone development.

In summary, we investigated a Chinese family with SYM1 and an unknown frameshift variant (c.635_636insG, p.Q213Pfs*57) was detected by whole exome sequencing. According to ACMG standards and guidelines, this variant was categorized as likely pathogenic (PM1, PM2, PM4, PP1, PP3 and PP4) and identified as the genetic lesion of the family. Our study expanded the spectrum of NOG mutations and contributed to genetic counseling and diagnosis of patients with SYM1.

Competing Interests

The authors declare that there are no competing interests associated with the manuscript.

Funding

This study was supported by the National Science and Technology Major Project of the Ministry of Science and Technology of China [grant number 2017ZX10103005-006]; the National Natural Science Foundation of China [grant number 81970403]; the Open Sharing Fund for the Large-scale Instruments and Equipments of Central South University [grant number CSUZC201940]; the Fundamental Research Funds of Central South University [grant number 2018zzts394] and the Emergency Project of Prevention and Control for COVID-19 of Central South University [grant number 160260003].

Author Contribution

Z.-Z.Y. and F.Y. carried out the sample collecting and genetic testing, J.-Y.J. and Z.-J.J. collected the clinical data, Z.-Z.Y. and J.-Y.J. performed the bioinformatics analysis, J.-Y.T. and R.X. designed the project and wrote the manuscript. All authors read and approved the final manuscript. All authors reviewed the manuscript.

Acknowledgements

We thank the patient and her parents for participating in this study. We thank Dr. Liang-Liang Fan performed genetic analysis assistance.

Abbreviations

     
  • ACMG

    The American College of Medical Genetics and Genomics

  •  
  • GDF5

    growth differentiation factor 5

  •  
  • gnomAD

    genome aggregation database

  •  
  • NOG

    noggin

  •  
  • OMIM

    Online Mendelian Inheritance in Man

  •  
  • SYM1

    proximal symphalangism

  •  
  • SYM1A

    proximal symphalangism-1A

  •  
  • SYM1B

    proximal symphalangism-1B

  •  
  • SYNS1

    multiple synostosis syndrome

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Author notes

*

These authors contributed equally to this work.

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