Table 1.
Causative mutations of skeletal disorders discovered since the most recent publication of the Nosology and Classification of Genetic Skeletal Disorders (149)
| Group | Disorder | Inheritance | MIM number | Locus | Gene | Notes/function |
|---|---|---|---|---|---|---|
| 9 | Short rib thoracic dysplasia (new form) | AR | NA | 5q23.2 | CEP120 (centrosomal protein, 120 kDa (124a) | Four separate families with same missense variant |
| 9 | Short-rib thoracic dysplasia 4 with or without polydactyly | AR | 613819 | 2q24.3 | TTC21B (Tetratricopeptide repeat domain-containing protein 21B) (29a) | Retrograde ciliary transport (IFT-A) |
| 9 15 |
Short-rib thoracic dysplasia 5 with or without polydactyly Cranioectodermal dysplasia 4 |
AR | 614376 614378 |
4p14 | WDR19 (WD-repeat containing protein 19) (22) | IFT-A complex, retrograde ciliary trafficking, ciliogenesis |
| 9 15 |
Short-rib thoracic dysplasia 7 with or without polydactyly Cranioectodermal dysplasia 2 |
AR | 614091 613610 |
2p24 | WDR35 (WD repeat-containing protein 35) (94) | Ciliogenesis and cilium maintenance |
| 9 | Short-rib thoracic dysplasia 8 with or without polydacyly | AR | 615503 | 7q36.3 | WDR60 (WD repeat-containing protein 60) (89) | Ciliogenesis, Hedgehog signaling |
| 9 | Short-rib thoracic dysplasia 9 with or without polydactyly | AR | 266920 | 16p13.3 | IFT140 (intraflagellar transport 140, Chlamydomonas, homolog of) (111) | Ciliogenesis, part of IFT-A complex (retrograde ciliary transport) |
| 9 | Short-rib thoracic dysplasia 10 with or without polydactyly | AR | 615630 | 2p23.3 | IFT172 (intraflagellar transport 172, Chlamydomonas, homolog of) (50) | Anterograde ciliary transport (IFT-B) |
| 9 | Short-rib thoracic dysplasia 11 with or without polydactyly | AR | 615633 | 9q32.11 | WDR34 (WD repeat-containing protein 34) (61, 123) | Retrograde ciliary transport (IFT-A), NF-κB signaling |
| 9 | Joubert syndrome 18 Orofaciodigital syndrome IV |
AR | 614815 258860 |
10q24.1 | TCTN3 (Tectonic family, member 3) (136) | Cilogenesis, Hedgehog signaling |
| 9 | Orofaciodigital syndrome V | AR | 174300 | 1q32.1 | DDX59 (DEAD box polypeptide 59) (127) | RNA helicase, RNA metabolism |
| 12 | Spondylometaphyseal dysplasia with cone-rod dystrophy | AR | 608940 | 3q29 | PCYT1A (phosphate cytidylyltransferase 1, choline, alpha isoform) (55, 154) | Phosphotidylcholine metabolism |
| 13 | Spondyloepimetaphyseal dysplasia with joint laxity, type 2 | AD | 603546 | 16p11.2 | KIF22 (Kinesin family member 22) (21, 95) | Unknown (speculated role in intracellular trafficking or ciliary transport) |
| 13 19 |
Spondyloepimetaphyseal dysplasia with joint laxity, type 2 Seckel Syndrome 7 |
AR | 603546 614851 |
14q22.1 | NIN (Ninein) (29, 47a) | Centrosome-mediated asymmetric cell division |
| 14 | Novel spondylodysplastic dysplasia | AR | NA | 16p13.3 | PAM16 (presequence translocase-associated motor 16) (90) | Mitochondrial transport |
| 14 | Opsismodysplasia | AD | 258480 | 11q13.4 |
INPPL1 (15, 60) Inositol polyphosphate phosphatase-like 1 |
PI3K-AKT signaling modulation |
| 15 | Acrodysostosis 1, with or without hormone resistance | AD | 101800 | 17q24.2 | PRKAR1A (protein kinase, cAMP dependent, regulatory, type 1, alpha) (86) | PKA/cAMP mediated signaling |
| 15 | Acrodysostosis 2, with or without hormone resistance | AD | 614613 | 5q12.1 | PDE4D (phosphodiesterase 4D) (83, 93) | Degradation of cAMP/inhibiting signaling pathway |
| 15 | Acromicric dysplasia Geleophysic dysplasia 2 |
AD AR |
102370 614185 |
15q21.1 | FBN1 (fibrillin 1) (79) | Integrin and TGF-β signaling |
| 18 | Bent bone dysplasia syndrome | AD | 614592 | 10q26.13 | FGFR2 (fibroblast growth factor receptor 2) (91) | Proper regulation of chondrocyte proliferation and differentiation |
| 19 | Microcephalic Primordial Dwarfism | AR | NA | 5q14.2 | XRCC4 (X-ray repair, complementing defective, in Chinese hamster, 4) (102a) | Nonhomologous end joining DNA repair |
| 19 | Microcephaly and chorioretinopathy, autosomal recessive, 2 | AR | 616171 | 4q28.2 | PLK4 (Polo-like kinase 4) (87b, 123c) | Centrosome duplication and maturation |
| 19 | New form of primordial dwarfism | AR | NA | 8q24.13 | NSMCE2 (non-SMC element 2 homolog) (110a) | E3 SUMO-ligase |
| 19 | Microcephaly 13, primary, autosomal recessive | AR | 616051 | 4q24 | CENPE (centromeric protein E) (96) | Kinetochore-associated chromosome alignment |
| 19 | Short stature, onychodysplasia, facial dysmorphism and hypotrichosis | AR | 614813 | 3p21.1–21.31 | POC1A (POC1 centriolar protein, Chlamydomonas, homolog of, A) (121, 124) | Centrosome maintenance, Golgi retrograde trafficking, proper mitotic spindle polarity, cilogenesis |
| 19 | IMAGe syndrome | AD, maternally imprinted | 614732 | 11p15 | CDKN1C (p57Kip2) (5) | Inhibition of cell cycle progression |
| 19 | Seckel syndrome 2 | AR | 606744 | 18q11.2 | RBBP8 (retinoblastoma-binding protein 8) (116) | DNA repair |
| 19 | Microcephalic osteodysplastic primordial dwarfism, type I | AR | 210710 | 2q14.2 | RNU4ATAC (RNA, U4ATAC small nuclear) (52, 37) | RNA splicing |
| 20 | Disorder of glycosylation resembling Desbuquois dysplasia | AR | NA | 6q14.1–14.2 | PGM3 (phosphoglucomutase 3) (134a) | Generates substrates for protein glycosylation |
| 20 | Desbuquois dysplasia 2 | AR | 615777 | 16p12.3 | XYLT1 (xylosyltransferase 1) (22a, 123a) | Glycosaminoglycan synthesis |
| 25 | Bone fragility with craniosynostosis, ocular proptosis, hydrocephalus, and distinctive facial features | AR | 112240 | 4q26 | SEC24D (SEC24-related gene family, member D) (43b) | Component of COPII-coated vesicles |
| 25 | Osteogenesis imperfecta, type V | AD | 610967 | 11p15.5 | IFITM5 (interferon-induced transmembrane protein 5) (26a, 123b) | Stimulates mineralization when overexpressed |
| 25 | Osteogenesis imperfecta, type XIII | AR | 614856 | 8p21.3 | BMP1 (bone morphogenetic protein 1) (7a, 87c) | BMP ligand |
| 25 | Osteogenesis imperfecta, type XIV | AR | 615066 | 9q31.2 | TMEM38B (transmembrane protein 38B) (123d) | Intracellular cation channel |
| 25 | Osteogenesis imperfecta type XV | AR | 615220 | 12q13.12 | WNT1 (wingless-type MMTV integration site family member 1) (68a) | WNT ligand |
| 25 | Osteogenesis imperfecta, type XVI | AR | 616229 | 11p11.2 | CREB3L1 (cAMP response element-binding protein 3–like 1) (134b) | Unfolded protein response |
| 30 | Proteus syndrome, somatic | AD, somatic mosaicism | 176920 | 14q32.33 | AKT1 (V-AKT murine thymoma ciral ocongene homolog 1) (85) | PI3K-AKT signaling, cell proliferation, cell growth |
| 32 | Yunis-Varon syndrome | AR | 216340 | 6q21 | FIG4 (FIG4, S. cerevisiae, homolog of) (24) | PI(3,5)P2 signaling |
| 35 | Klippel-Feil syndrome 2 | AR | 214300 | 17q21.31 | MEOX1 (mesenchyme homeobox 1) (98) | Transcription factor involved in somitogenesis |
| 36 | Genitopatellar syndrome SBBYSS syndrome |
AD | 606170 603736 |
10q22.2 | KAT6B (lysine acetyltransferase 6B) (23, 27) | Histone acetyltransferase |
| 36 | Meier-Gorlin syndrome 1 | AR | 224690 | 1p32.3 | ORC1 (origin recognition complex, subunit 1, S. cerevisiae, homolog of) (17, 16) | ORC subunit, DNA replication |
| 36 | Meier-Gorlin syndrome 2 | AR | 613800 | 2q22.3–23.1 | ORC4 (origin recognition complex, subunit 4, S. cerevisiae, homolog of) (49) (16) | ORC subunit, DNA replication |
| 36 | Meier-Gorlin syndrome 3 | AR | 613803 | 16q11.2 | ORC6 (origin recognition complex, subunit 6, S. cerevisiae, homolog of) (16) | ORC subunit, DNA replication |
| 36 | Meier-Gorlin syndrome 4 | AR | 613804 | 16q24.3 |
CDT1 (16) Chromatin licensing and DNA replication factor 1 |
Recruited to fully assembled prereplication complex |
| 36 | Meier-Gorlin syndrome 5 | AR | 613805 | 17q21.2 | CDC6 (cell division cycle 6, S. cerevisiae, homolog of) (16) | Recruited to fully assembled prereplication complex |
| 37 | Myhre syndrome | AD | 139210 | 18q21.2 | SMAD4 (mothers against decapentalplegic, Drosophila, homolog of, 4) (78) | TGF-β and BMP signaling modulation |
| 37 | Feingold syndrome 2 | AD | 614326 | 13q31.3 | MIR17HG (micro RNA 17 host gene) (31) | miRNA cluster transcriptionally regulated by N-MYC |
| 39 | Meckel syndrome 2 | AR | 603194 | 11p12–q13.3 | TMEM216 (transmembrane protein 216) (140) | Ciliogenesis, cilium maintenance, planar-cell polarity signaling |
| 39 | Meckel syndrome 10 | AR | 614175 | 19q13.2 | B9D2 (B9 domain–containing protein 2) (35) | Ciliogenesis, ciliary protein localization, Hedgehog signaling |
| 39 | Joubert syndrome 21 | AR | 615636 | 8q13.1–13.2 | CSPP1 (centrosome spindle pole associate protein 1) (2, 125, 139) | Some patient phenotypes resembled Meckel syndrome |
| ? | New syndrome with short stature and several additional clinical features, including neurodegeneration and photosensitivity | AR | NA | 20p13–p12 | PCNA (proliferating cell nuclear antigen) (10b) | Required for DNA repair |
Abbreviations: AD, autosomal dominant; AR, autosomal recessive; BMP, bone morphogenetic protein; IMAGe, intraunterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital abnormalities; MIM, Mendelian Inheritance in Man; miRNA, microRNA; NA, not applicable; ORC, origin recognition complex; PI3K, phosphoinositide 3-kinase; SBBYS, Say-Barber-Biesecker-Young-Simpson.