Proximal symphalangism is a rare disease with multiple phenotypes including reduced proximal interphalangeal joint space, symphalangism of the 4th and/or 5th finger, as well as hearing loss. At present, at least two types of proximal symphalangism have been identified in the clinic. One is proximal symphalangism-1A (SYM1A), which is caused by genetic variants in Noggin (NOG), another is proximal symphalangism-1B (SYM1B), which is resulted from Growth Differentiation Factor 5 (GDF5) mutations.
Case presentation
Here, we reported a Chinese family with symphalangism of the 4th and/or 5th finger and moderate deafness. The proband was a 13-year-old girl with normal intelligence but symphalangism of the 4th finger in the left hand and moderate deafness. Hearing testing and inner ear CT scan suggested that the proband suffered from structural deafness. Family history investigation found that her father (II-3) and grandmother (I-2) also suffered from hearing loss and symphalangism. Target sequencing identified a novel heterozygous NOG mutation, c.690C > G/p.C230W, which was the genetic lesion of the affected family. Bioinformatics analysis and public databases filtering further confirmed the pathogenicity of the novel mutation. Furthermore, we assisted the family to deliver a baby girl who did not carry the mutation by genetic counseling and prenatal diagnosis using amniotic fluid DNA sequencing.
Conclusion
In this study, we identified a novel NOG mutation (c.690C > G/p.C230W) by target sequencing and helped the family to deliver a baby who did not carry the mutation. Our study expanded the spectrum of NOG mutations and contributed to genetic diagnosis and counseling of families with SYM1A.
Hinweise
Cong Ma and Lv Liu contributed equally to this work.
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Abkürzungen
BMPs
Bone morphogenetic proteins
GDF5
Growth Differentiation Factor 5
kb
Kilobases
NOG
Noggin
SYM1A
proximal symphalangism-1A
SYM1B
proximal symphalangism-1B
Background
Proximal symphalangism is a rare genetic disorder of congenital limb malformation, characterized by ankylosis of the proximal interphalangeal joints, carpal and tarsal bone fusion, and, in some cases, conductive deafness and premature ovarian failure [1, 2]. The typical features of proximal symphalangism are reduced proximal interphalangeal joint space, symphalangism of the 4th and/or 5th finger [3, 4]. As early as in 1916, Cushing has described an American family with ankylosis of the proximal interphalangeal joints, and he named this heterozygote autosomal dominant disease as symphalangism [5].
At present, there are two types of diseases in the proximal symphalangism family: (1) Proximal symphalangism-1A (SYM1A, OMIM # 185800), which iss caused by genetic variants in Noggin (NOG) [6, 7]; (2) Proximal symphalangism-1B (SYM1B), which is resulted from Growth Differentiation Factor 5 (GDF5) mutations [8, 9]. In addition, some other diseases may be also related to proximal symphalangism, such as tarsal-carpal coalition syndrome, multiple synostoses syndrome, and brachydactyly, etc. [10, 11].
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In this study, we employed target sequencing to explore the genetic lesion of a Chinese family with symphalangism of the 4th and/or 5th finger and moderate deafness. A novel mutation (c.690C > G/p.C230W) of NOG was identified in all affected individuals in this family. Furthermore, after genetic counseling and prenatal diagnosis with us, the mother successfully delivered a baby girl who did not carry the mutation.
Case presentation
A family from North of China (Hebei Province) with eight members across three generations participated in the study (Fig. 1a). The proband (III-2) was a 13-year-old girl with normal intelligence but symphalangism of the 4th finger in the left hand (Fig. 1b) and moderate deafness (Fig. 1c). Inner ear CT scan found abnormal inner ear structure (cochlear hypoplasia) and abnormal calcification (inner ear bone thickening and increased density) (Fig. 1d). Family history investigation found that her father (II-3) and grandmother (I-2) also suffered from hearing loss and symphalangism (Fig. 1a, e). Her grandmother has died six years ago. Her father showed the symphalangism of the 4th finger in left hand (Fig. 1e, f). He had performed the vestibulotomy and recovered the hearing one year ago. They went to the Department of Reproductive Genetics, HeBei General Hospital because the mother was pregnant with the second baby. They wanted to detect whether the second baby was normal or not.
Fig. 1
The Clinical data of the family. a The pedigree of this family. Black circles/squares are affected, white circles/squares are unaffected. N means Normal, M indicates Mutation. Arrow indicates the proband. b The proband showed the symphalangism of the 4th finger in the left hand. c Hearing testing suggests the proband suffering from moderate deafness. d Inner ear CT showed abnormal inner ear structure and abnormal calcification. The red circles marked the abnormal regions which indicated cochlear hypoplasia, inner ear bone thickening and increased density. e The symphalangism of the 4th finger in II-3. f Hands X-ray of III-2. The red circles marked the abnormal regions
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Genetic analysis
We selected the proband’s genomic DNA to perform the target sequencing to detect the disease-causing mutations by Sinopath Diagnosis Company (Beijing, China). Target sequencing yielded 3.71 Gb of data with 99.088% coverage of the target region and 97.530% of the target covered over 10×. After filtering dbSNP132, 1000G, EXAC, and GenomAD database (MAF < 0.01), only 12 mutation were left. We then conducted the co-segregation analysis by Sanger sequencing and only seven variants were exist in affected individuals and were absent in healthy members (Table 1). We further performed the bioinformatics analysis including MutationTaster, SIFT, Polyphen-2, PANTHER, ToppGene function analysis, OMIM clinical phenotype analysis and ACMG classification (Table 1), we highly suspected the novel mutation (c.690C > G/p.C230W) of NOG, belonging to PM1 and PM2 in ACMG guidelines [12], was responsible for the family with SMY1A. This mutation resulted in a substitution of in polar amino acid cysteine by nonpolar amino acid tryptophan in the codon 230 of exon 1 of NOG gene, and was not presented in our 200 control cohorts. Noggin amino acid sequence alignment analysis suggested that this mutation was located in a highly evolutionarily conserved site (Fig. 2b). In addition, we also constructed a part model of the Noggin protein using SWISS-MODEL (https://swissmodel.expasy.org) (Fig. 2c) and, after applying SDM software (http://marid.bioc.cam.ac.uk/sdm2/prediction) to analyze the structure, it was found that this novel mutation might increase the solvent accessibility (WT:16.9% and Mutant: 39.9%) and reduce the stability of the Noggin protein.
Table 1
The mutations list after data filtering and co-segregation analysis
CHR Chromosome, POS position, RB reference sequence base, AB alternative base identified, D damaging, P probably damaging, B Benign, T Tolerated, AR autosomal recessive, AD autosomal dominant, BP Benign Supporting, PM Pathogenicity Moderate
Fig. 2
Genetic analysis of the family. a Sanger DNA sequencing chromatogram demonstrates the heterozygosity for a NOG mutation (c.690C > G/p.C230W). b Analysis of the mutation and protein domains of Noggin. The C230 affected amino acid locates in the highly conserved amino acid region in different mammals (from Ensembl). The black arrow and red words show the C230 site. c Swiss-model analyzed the Noggin structures of WT and Mutated (p.C230W). d The healthy hands of III-3 and normal sequences of amniotic fluid DNA
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Prenatal diagnosis
When the parents came to our hospital, the mother has been pregnant with the second baby for 17 weeks and they wanted to have a healthy baby. According to ACMG classification, the novel mutation (c.690C > G/p.C230W) of NOG belongs to PM1 and PM2. Simultaneously, target sequencing only identified this mutation as a pathogenic variant. So, we highly believed the novel mutation (c.690C > G/p.C230W) of NOG was the genetic lesion of the family with proximal symphalangism and hearing loss. We then performed the Sanger sequencing of amniotic fluid DNA to detect the mutation, fortunately, the results showed a normal allele of the second baby. And 22 weeks later, the mother delivered a 3.4-kg healthy girl (Fig. 2d).
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Discussion
The human NOG gene encoding Noggin protein is located on chromosome 17q22, and it consists of one exon, spanning approximately 1.9 kilobases (kb) [6]. Noggin protein is involved in the development of many body tissues, including nerve tissue, muscles, and bones and the role of Noggin in bone development makes it significant for proper joint formation [13]. According to previous researches, Noggin protein can interact with bone morphogenetic proteins (BMPs) and regulate the development of bone and other tissues [14]. In detail, the Noggin protein regulates the activity of BMPs by binding to them and blocking them from attaching to the downstream receptor, which results in a decrease in BMP signaling [15]. In our research, the novel mutation (c.690C > G/p.C230W) of NOG can increase the solvent accessibility and reduce the stability of the Noggin, which may active the BMP signal pathway and lead to bone diseases.
In 1999, five NOG mutations were identified in unrelated families with symphalangism (SYM1A) and a de novo mutation in a patient with unaffected parents [6]. Interestingly, a wide variety of bone development anomalies, including tarsal/carpal coalition syndrome [10], brachydactyly [16], multiple synostoses syndrome [17], Stapes ankylosis with broad thumbs and toes [18], have been reported in patients with NOG mutations. Similar observations were also reported in the families even with the same mutation [16, 19]. Therefore, the pleiotropic types of bone diseases and significant genetic heterogeneity make it difficult to be diagnosed. We summarized the previous reports and found that approximately 57 mutations (60 patients) of NOG have been identified in different types of disorders (Table 2).
Table 2
The summary of reported mutations of NOG
No.
Mutation
Phenotypes
Reference
1
p. Leu20fs
Multiple synostoses syndrome
Takahashi et al. (2001)
2
p. Pro35Ala
Brachydactyly type B
Lehmann et al. (2007)
3
p. Pro35Ser
Teunissen-Cremers syndrome
Hirshoren et al. (2008)
4
p. Pro35Ser
Proximal symphalangism
Mangino et al. (2002)
5
p. Pro35Ser
Brachydactyly type B
Lehmann et al. (2007)
6
p. Pro35Arg
Proximal symphalangism
Gong et al. (1999)
7
p. Pro35Arg
Tarsal–carpal coalition syndrome
Dixon et at. (2001)
8
p. Ala36Pro
Brachydactyly type B
Lehmann et al. (2007)
9
p. Pro37Arg
Tarsal–carpal coalition syndrome
Debeer et al. (2004)
10
p. Pro42Ala
Multiple synostoses syndrome
Debeer et al. (2005)
11
p. Pro42Ser
Proximal symphalangism
Sha et al. (2019)
12
p. Pro42Arg
Multiple synostoses syndrome
Oxley et al. (2008)
13
p. Pro42Thr
Multiple synostoses syndrome
Aydin, H et al. (2013)
14
p. Val44fs
Teunissen-Cremers syndrome
Weekamp et al. (2005)
15
p. Glu48Lys
Brachydactyly type B
Lehmann et al. (2007)
16
p. Glu48Lys
Proximal symphalangism
Kosaki et al. (2004)
17
p. Pro50Arg
Tarsal–carpal coalition syndrome
Debeer et al. (2005)
18
p. Asp55Tyr
Proximal symphalangism
Xiong et al. (2019)
19
p. Glu85fs
Stapes ankylosis with broad thumb and toes
Brown et al. (2002)
20
p. Arg87fs
Multiple synostoses syndrome
Lee et al. (2014)
21
p. Gly91Cys
Fibrodysplasia ossificans progressiva
Kaplan et al. (2008)
22
p. Gly92Arg
Fibrodysplasia ossificans progressiva
Kaplan et al. (2008)
23
p. Gly92Glu
Fibrodysplasia ossificans progressiva
Kaplan et al. (2008)
24
p. Ala95Thr
Fibrodysplasia ossificans progressiva
Kaplan et al. (2008)
25
p. Ala102fs
Proximal symphalangism
Thomeer et al. (2011)
26
p. Gln110X
Stapes ankylosis with broad thumb and toes
Brown et al. (2002)
27
p. Leu129X
Proximal symphalangism
Takahashi et al. (2001)
28
p.Gln131X
Stapes ankylosis with broad thumbs and toes
Takashi etal. (2014)
29
p. Lys133X
Stapes ankylosis with broad thumb and toes
Takano et al. (2016)
30
p. Arg136Cys
Proximal symphalangism
Masuda et al. (2014)
31
p. Trp150Cys
Proximal symphalangism
Pan et al. (2015)
32
p. Cys155Phe
Stapes ankylosis with symphalangism
Usami et al. (2012)
33
p. Cys155Ser
Proximal symphalangism
Usami et al. (2012)
34
p. Arg167Gly
Brachydactyly type B
Lehmann et al. (2007)
35
p. Arg167Cys
Proximal symphalangism
Liu et al. (2015)
36
p. Cys184Tyr
Proximal symphalangism
Takahashi et al. 2001
37
p. Cys184Phe
Proximal symphalangism
Usami et al. 2012
38
p. Pro187Ser
Brachydactyly type B
Lehmann et al. (2007)
39
p. Pro187Ala
Proximal symphalangism
Ganaha et al. (2015)
40
p. Glu188fs
Teunissen-Cremers syndrome
Weekamp et al. (2005)
41
p. Gly189Cys
Proximal symphalangism
Gong et al. (1999)
42
p. Met190Val
Multiple synostoses syndrome
Oxley et al. (2008)
43
p. Leu203Pro
Teunissen-Cremers syndrome
Weekamp et al. (2005)
44
p. Arg204Leu
Tarsal/carpal coalition syndrome
Dixon et al. (2001)
45
p. Arg204Gln
Tarsal-carpal coalition syndrome
Das et al. (2018)
46
p. Trp205X
Multiple synostoses syndrome
Dawson et al. (2006)
47
p. Trp205Cys
Facioaudiosymphalangism syndrome
van den Ende et al. (2005)
48
p. Trp205fs
Stapes ankylosis with broad thumb and toes
Emery et al. (2009)
49
p. Cys215X
Stapes ankylosis with broad thumb and toes
Usami et al. (2012)
50
p. Trp217Gly
Multiple synostoses syndrome
Gong et al. (1999)
51
p. Ile220Asn
Proximal symphalangism
Gong et al. (1999)
52
p. Ile220fs
Proximal symphalangism
Gong et al. (1999)
53
p. Tyr222Asp
Proximal symphalangism
Gong et al. (1999)
54
p. Tyr222Cys
Proximal symphalangism
Gong et al. (1999)
55
p. Tyr222Cys
Tarsal–carpal coalition syndrome
Dixon et al. (2001)
56
p. Pro223Leu
Proximal symphalangism
Gong et al. (1999)
57
p. Cys228Gly
Stapes ankylosis with broad thumb and toes
Ishino et al. (2015)
58
p. Cys228Ala
Multiple synostoses syndrome
Ganaha et al. (2015)
59
p. Cys230Tyr
Multiple synostoses syndrome
Bayat et al. (2016)
60
p. Cys230Trp
Proximal symphalangism
Present study
61
p. Cys232Trp
Multiple synostoses syndrome
Rudnik-Schöneborn et al. (2010)
Bold words indicate the patients with deafness
In this study, a family with symphalangism and moderate deafness was investigated by target sequencing. Genetic analysis found a novel mutation (c.690C > G/p.C230W) of NOG in two affected members. Of note, both of two patients with p.C230W in the family were associated with hearing loss. To date, 29 mutations have been reported in symphalangism patients related to deafness (Table 2) [11]. And the mutation p.C230W was the fifth report related to NOG mutation, although some Chinese journals have also published some reported mutations. Meanwhile, this difference also suggested that there were still a lot of novel mutations need to discovery in Chinese population.
The p.C230W mutation disrupts the cysteine knot motif of the C-terminal domain of Noggin (amino acids 155–232), which contains a series of nine cysteine residues and was shown to target the molecule to a specific receptor protein [20, 21]. The similar mutations (p.C228G, p.C228S, p.C230Y and p.C232W) have been identified in patients with symphalangism and hearing loss, which indicated that mutations in cysteine residues may be related to abnormal development of auditory ossicles and hearing loss [19, 22‐24].
In clinical genetics, the aim of mutation detection is to make contributions to genetic diagnosis and counseling. In this study, we identified the genetic lesion of the family by target sequencing. All the filtered data were shown in Table 1. We not only performed the informatics analysis of the novel mutation by multi-different algorithm based bioinformatics programs, but also followed the ACMG guidelines to estimate the pathogenicity of the novel mutation strictly (PM1 and PM2). Finally, we highly believed that the novel mutation (p.C230W) of NOG may be the genetic lesion of the family. We then assisted the family to get a healthy baby by amniotic fluid DNA sequencing referring to other people’s research [25]. Prenatal diagnosis not only helped the patient to delivery healthy baby and improved the population quality but also relieved psychological and financial stress [26]. Our study provided a successful example for genetic counseling and prenatal diagnosis of patients with SYM1A.
Conclusions
We reported a novel NOG mutation (c.690C > G/p.C230W) in a three-generation family with SYM1A. And we helped them delivery a girl baby who did not carry the mutation by genetic counseling and prenatal diagnosis. Our study not only presented the important role of NOG in proximal symphalangism and deafness but also expanded the spectrum of NOG mutations and contributed to genetic diagnosis and counseling of families with SYM1A.
Acknowledgements
We thank all subjects for participating in this study.
Ethics approval and consent to participate
Written informed consent was obtained from each individual and the investigation was approved by the Institutional Review Board of HeBei General Hospital.
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Consent for publication
Written consent was obtained from all the participants or their guardians for the publication of this study.
Competing interests
The authors declare that they have no competing interests.
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