Background
Proximal symphalangism (SYM1; MIM# 185800) is a rare condition characterized by ankylosis of proximal interphalangeal joints (PIP, those between the first (also called proximal) and second (intermediate) phalanges) in fingers and toes, due to carpal and tarsal bone fusion [
1]. In some affected individuals, fusions are concomitant with conductive hearing loss [
2‐
5], hypermetropia [
6‐
8], deformed facies [
7], absence of digit flexion creases [
1,
9], curtate metacarpals, and semideveloped distal phalanges [
7,
10‐
12].
SYM1 appears to be an autosomal dominant disorder with prominent familial inheritance characteristics [
13‐
15]. Two potential pathogenic genes have been identified in SYM1 patients: noggin (
NOG, MIM# 602991) and
GDF5 (MIM# 601146).
NOG mutations are the main cause of SYM1, accounting for most case reports of this disease.
Here, we investigated a four-generation non-consanguineous Chinese family with SYM1. Whole exome sequencing revealed a novel heterozygous missense mutation in NOG. Our findings expanded current understanding of the relationship between NOG mutations and SYM1. Overall, this work provides more insight on SYM1 for researchers and clinicians.
Discussion
Patients in the studied four-generation non-consanguineous family exhibited PIP-joint fusion and talonavicular synostosis without conductive hearing loss, consistent with SYM1. Whole genome sequencing identified a novel missense mutation c.124C > T, p.(Pro42Ser) of NOG in these patients, suggesting that this mutation may be the main cause of these patients.
The
NOG gene (~ 1892 bp) is located on chromosome 17q22 and has only one exon. The gene product is noggin, a 232-amino-acid protein with a molecular mass of 25.774 kDa. The Human Gene Mutation Database has records of multiple
NOG mutations associated with several disease, including SYM1 [
2,
21,
22], brachydactyly type B2 (BDB2) [
3,
7,
23], multiple synostoses syndrome 1 (SYNS1, [
7,
13]) stapes ankylosis with broad thumbs and toes (SABTT) [
3,
22], and tarsal–carpal coalition syndrome (TCC) [
7,
24,
25]. Additional file
3 summarizes all known
NOG mutations that cause symphalangism and related symptoms.
Noggin plays an essential role in cartilage morphogenesis and joint formation [
14,
26]. Noggin action occurs through competitive binding with BMP receptors. Due to this function,
NOG mutations are also commonly associated with conductive hearing loss due to auditory-ossicle fusion [
2,
3,
5,
21]. However, our novel c.124C > T, p.(Pro42Ser) mutation did not cause conductive hearing loss, consistent with several previously reported mutations: c. 435C > G, p.(Pro42Arg), c.125C > T, p.(Pro42Leu), and c.124 C > A, p.(Pro42Thr) [
27‐
29]. We note that while two elderly patients (II:1 and II:4) exhibited slight hearing loss, they reportedly had normal hearing when young, suggesting an effect of age rather than genetic mutation. Overall, mutations at the 42nd position does not appear to cause conductive hearing loss. Thus, this symptom is probably closely linked to the exact location of a given
NOG mutation. More studies are necessary to verify this hypothesis.
Although variants at the amino acid residue of Pro42 did not lead to conductive hearing loss, the symptoms of the patients were diverse. Patients carrying c.435C > G, p.(Pro42Arg) mutations had characteristic facial features of symphalangism, including a hemi-cylindrical nose. One patient exhibited additional features, including ankylosis of proximal and middle phalanges of the hands. Detailed anthropometry revealed relative macrocephaly and shortened spines in affected individuals [
28]. Patients carrying c.125C > T, p.(Pro42Leu) mutations presented facial dysmorphism; bulbous nasal tip with a flat nasal bridge; mild hypoplasia of distal fingers with short, flat nails; symphalangism of PIP joints; hypoplasia of middle phalanges; and carpal bone fusion. Radiographs of the feet revealed hypoplastic middle phalanges, talonavicular fusion, osseous fusions of cuneiforms with metatarsals, and cuboid bone absence [
27]. Patients with c. 124 C > A, p.(Pro42Thr) mutations exhibit multiple synostoses syndrome (MSS), facial dysmorphism, brachydactylic fingers, as well as incomplete syndactyly of the second, third, and fourth web spaces. Fingers and PIP joins did not present flexion creases, leading to absence of movement in the latter. One patient’s right hand exhibited symphalangism of the third and fourth fingers, while her left hand exhibited symphalangism of the fourth and fifth fingers. In addition, she had a coalition of the trapezium and the first metacarpal [
29]. Compared with the other three Pro42 mutations, our novel mutation c.124C > T, p.(Pro42Ser) only led to proximal symphalangism in hands and feet, without any facial dysmorphism. The facial dysmorphism was also not observed in the other studies of Chinese patients with NOG mutations [
1,
21,
30,
31]. Together, these findings suggested that
NOG mutations does not cause facial deformity in individuals of Chinese descent, possibly due to differences in their facial features from people in Europe and America.
In this study, we found evidence that the proline-to-serine mutation may affect binding chain structure in noggin. In turn, noggin binding capacity with other signaling proteins, such as BMPs and GDFs, may be affected. This change may exert a smaller effect than other mutations, perhaps partly explaining why c.124C > T, p.(Pro42Ser) caused only proximal symphalangism without other symptoms.
Conclusions
In summary, we identified a novel heterozygous NOG mutation c.124C > T, p.(Pro42Ser) in a four-generation non-consanguineous Chinese family with SYM1. The affected amino acid was highly conserved across species. The proline-to-serine change resulting from the mutation may alter noggin binding-chain structure, thus influencing noggin binding capacity. Overall, our results indicate that c.124C > T, p.(Pro42Ser) mutation is highly pathogenic and may be the main cause of SYM1 in this family. Our findings broaden the NOG mutation spectrum associated with SYM1, clarifying the genetic origins of this condition for the benefit of researchers and clinicians.
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