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1.
Clin Genet ; 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31600839

RESUMO

Aymé-Gripp syndrome (AYGRPS) is a recognizable condition caused by a restricted spectrum of dominantly acting missense mutations affecting the transcription factor MAF. Major clinical features of AYGRPS include congenital cataracts, sensorineural hearing loss, intellectual disability, and a distinctive flat facial appearance. Skeletal abnormalities have also been observed in affected individuals, even though, these features have not been assessed systematically. Expanding the series with four additional patients, here we provide a more accurate delineation of the molecular aspects and clinical phenotype, particularly focusing on the skeletal features characterizing this disorder. Beside previously reported malar flattening and joint limitations, we document that carpal/tarsal and long bone defects, and hip dysplasia occur in affected subjects more frequently than formerly appreciated. This article is protected by copyright. All rights reserved.

2.
J Hum Genet ; 64(10): 1041-1044, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31388108

RESUMO

Mesomelic dysplasia (MD) encompasses a heterogeneous group of disorders characterized by shortening of the middle segments of the limbs. Previous studies have revealed the development of Nievergelt type-like MD accompanied by postaxial toe reduction in a patient with a ~500 kb microdeletion at 2q11.2 involving AFF3 alone, and the occurrence of Nievergelt type-like MD in mice with a ~353 kb deletion involving Aff3, together with strong expression of mouse Aff3 in the developing limbs and zeugopod. We encountered a 2 6/12-year-old Japanese girl with an unclassifiable MD associated with hypoplasia of postaxial toes, and identified a de novo likely pathogenic variant of AFF3 (NM_002285.2:c.697 G > A, p.(Ala233Thr)) by whole exome sequencing. The results provide further evidence for AFF3 being the causative gene for MD with foot malformation which may be termed "AFF3-related MD" or "Steichen-Gersdorf type MD".

3.
Eur J Hum Genet ; 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31332306

RESUMO

Split-hand/foot malformation (SHFM) is a clinically and genetically heterogeneous condition. We sequentially performed screening of the previously identified Japanese founder 17p13.3 duplication/triplication involving BHLHA9, array comparative genomic hybridization, and whole exome sequencing (WES) in newly recruited 41 Japanese families with non-syndromic and syndromic SHFM. We also carried out WES in seven families with nonsyndromic and syndromic SHFM in which underlying genetic causes including pathogenic copy-number variants (CNVs) remained undetected in our previous studies of 56 families. Consequently, we identified not only known pathogenic CNVs (17p13.3 duplications/triplications [n = 21], 2q31 deletion [n = 1], and 10q24 duplications [n = 3]) and rare variants in known causative genes (TP63 [n = 3], DLX5 [n = 1], IGF2 [n = 1], WNT10B [n = 3], WNT10B/PORCN [n = 1], and PORCN [n = 1]), but also a de novo 19q13.11 deletion disrupting UBA2 (n = 1) and variants that probably affect function in LRP6 (n = 1) and UBA2 (n = 1). Thus, together with our previous data based on testing of 56 families, molecular studies for a total of 97 families with SHFM revealed underlying genetic causes in 75 families, and clinical studies for the 75 families indicated a certain degree of correlation between genetic causes and phenotypes. The results imply that SHFM primarily occurs as a genetic disorder with genotype-phenotype correlations. Furthermore, the results together with previous data such as the development of SHFM in Lrp6 knockout mice, the presence of SHFM in two subjects with 19q13 deletions involving UBA2, and strong mouse Uba2 expression in the developing limb buds, imply that LRP6 and UBA2 represent plausible candidate genes for SHFM.

4.
BMC Med Genet ; 20(1): 126, 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31311520

RESUMO

BACKGROUND: Osteodysplasia of the oral and maxillofacial bone is generally accompanied by systemic bone abnormalities (such as short stature, joint contracture) or other systemic abnormalities (such as renal, dermatological, cardiovascular, optic, or hearing disorders). However, it does not always present this way. Recent reports have suggested that genome-wide sequencing is an effective method for identifying rare or new disorders. Here, we performed whole-exome sequencing (WES) in a patient with a unique form of acquired, local osteodysplasia of the oral and maxillofacial region. CASE PRESENTATION: A 46-year-old woman presented to our hospital with the complaint of gradually moving mandibular teeth (for 6 months), changing facial appearance, and acquired osteolysis of the oral and maxillofacial bones, showing mandibular hypoplasia without family history. Upon skeletal examination, there were no abnormal findings outside of the oral and maxillofacial area; the patient had a height of 157 cm and bone mineral density (according to dual energy x-ray absorptiometry) of 90%. Results of blood and urine tests, including evaluation of bone metabolism markers and neurological and cardiovascular examinations, were normal. We performed WES of genomic DNA extracted from the blood of this patient and her mother, who did not have the disease, as a negative control. We identified 83 new missense variants in the patient, not detected in her mother, including a candidate single nucleotide variant in exon 14 of PCNT (pericentrin). Critical homozygous or compound heterozygous variants in PCNT are a known cause of microcephalic osteodysplastic primordial dwarfism type II accompanied by mandibular hypoplasia, which is similar to the maxillofacial phenotype in this patient. CONCLUSIONS: Protein simulations performed using Polymorphism Phenotyping v2 and Combined Annotation Dependent Depletion software indicated that this missense variant is likely to disrupt the PCNT protein structure. These results suggest that this is a new form of osteolysis related to this PCNT variant.

5.
Pediatr Int ; 61(8): 748-753, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31247124

RESUMO

BACKGROUND: Thanatophoric dysplasia (TD) is a rare congenital disease of the skeletal system, with an incidence of 1.68-8.3 per 100 000 births, but statistical data on the estimated number of TD patients across Japan are not available. The aim of this study was therefore to investigate the prevalence and prognosis of TD in Japan. METHODS: A nationwide primary questionnaire survey was conducted. RESULTS: A total of 127 obstetric, 186 pediatric, and 115 orthopedic facilities provided responses. Excluding duplications, we identified 73 patients with TD. Of the 73 cases, 15 were abortions, four were stillbirths, 51 were live births, and three had unknown details. Of the 51 live newborns, 27 died ≤7 days after birth, with an early neonatal mortality rate of 56%. Of the 24 newborns who survived the early neonatal period, 16 survived for ≥1 year. All of the 24 newborns received respiratory management and survived during the early neonatal period. Of the 51 live newborns, 25 did not receive respiratory management and died ≤2 days after birth. CONCLUSIONS: The prevalence of TD in Japan is estimated to be at 1.1 (95%CI: 0.84-1.37) per 100 000 births, but the actual incidence is expected to be higher. To our knowledge, we have confirmed for the first time that newborns with TD may not always die during the early neonatal period but can survive the early neonatal period with appropriate respiratory management. Therefore, the term "thanatophoric dysplasia" does not accurately reflect the nature of the disease.

6.
J Bone Miner Res ; 2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31163101

RESUMO

Dysosteosclerosis (DOS) is a distinct form of sclerosing bone disease characterized by irregular osteosclerosis and platyspondyly. DOS is genetically heterogeneous; however, only five cases with SLC29A3 mutations and a single case with a splice-site mutation of TNFRSF11A have been reported, and TNFRSF11A is also a causal gene for osteopetrosis, autosomal recessive 7 (OP-AR7). Thus, the causal genes of DOS and their genotype-phenotype associations remain unclear. In this study, we examined a Japanese patient with DOS and found a novel variant in TNFRSF11A. The homozygous variant was a G to T transversion at the first nucleotide of exon 9 (c.784G>T). Although the variant was predicted to cause a stop codon mutation (p.E262*), in silico evaluation of the exonic splicing elements followed by RT-PCR for the patient-derived cells showed that it caused aberrant splicing due to the change in the exonic splicing element and produced two types of aberrant transcripts: One caused a premature stop codon (p.E262Vfs*17) leading to nonsense mutation-mediated mRNA decay; the other produced a protein with interstitial deletion (p.E262_Q279del). The effects of the mutation on five splicing isoforms of TNFRSF11A were different from those in OP-AR7, but comparable with those in the first DOS with the TNFRSF11A mutation. Thus, we identified the second case of DOS caused by the TNFRSF11A splice-site mutation and confirmed the novel disease entity. © 2019 American Society for Bone and Mineral Research.

7.
Am J Hum Genet ; 104(5): 925-935, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-30982609

RESUMO

Colony stimulating factor 1 receptor (CSF1R) plays key roles in regulating development and function of the monocyte/macrophage lineage, including microglia and osteoclasts. Mono-allelic mutations of CSF1R are known to cause hereditary diffuse leukoencephalopathy with spheroids (HDLS), an adult-onset progressive neurodegenerative disorder. Here, we report seven affected individuals from three unrelated families who had bi-allelic CSF1R mutations. In addition to early-onset HDLS-like neurological disorders, they had brain malformations and skeletal dysplasia compatible to dysosteosclerosis (DOS) or Pyle disease. We identified five CSF1R mutations that were homozygous or compound heterozygous in these affected individuals. Two of them were deep intronic mutations resulting in abnormal inclusion of intron sequences in the mRNA. Compared with Csf1r-null mice, the skeletal and neural phenotypes of the affected individuals appeared milder and variable, suggesting that at least one of the mutations in each affected individual is hypomorphic. Our results characterized a unique human skeletal phenotype caused by CSF1R deficiency and implied that bi-allelic CSF1R mutations cause a spectrum of neurological and skeletal disorders, probably depending on the residual CSF1R function.

8.
Clin Genet ; 95(6): 713-717, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30847897

RESUMO

Desbuquois dysplasia (DBQD) is an autosomal recessive heterogeneous disorder characterized by joint laxity and skeletal changes, including a distinctive monkey-wrench appearance of the femora, advanced carpal ossification, and abnormal patterning of the preaxial digits. Two genes for DBQD (CANT1 encoding calcium-activated nucleotidase-1 and XYLT1 encoding xylosyltransferase-1) have been reported. We propose a novel gene for neonatal short limb dysplasia resembling DBQD, based on the phenotype and genotype of two affected siblings. The affected boy and girl died in early infancy and shortly after birth, respectively. The clinical hallmarks included mid-face hypoplasia, thoracic hypoplasia with respiratory failure, very short stature (approximately -7 SD of birth length) with mesomelic shortening of the limbs, and multiple dislocations of the large joints. Radiological examinations showed prominent lesser trochanter, flared metaphyses of the long bones, and joint dislocations. The affected boy had preaxial digital hypoplasia, and the affected girl showed overlapping and syndactyly of the preaxial digits. Molecular analyses of the girl showed compound heterozygous variants in FAM20B (NM_014864: c.174_178delTACCT p.T59Afs*19/c.1038delG p.N347Mfs*4). FAM20B encodes glycosaminoglycan xylosylkinase, which acts downstream of xylosyltransferase-1. Given the fact that FAM20B deficiency causes skeletal phenotypes in mice and zebrafish, these variants are highly probable to be pathogenic.

9.
JCI Insight ; 4(3)2019 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-30728324

RESUMO

Odontochondrodysplasia (ODCD) is an unresolved genetic disorder of skeletal and dental development. Here, we show that ODCD is caused by hypomorphic TRIP11 mutations, and we identify ODCD as the nonlethal counterpart to achondrogenesis 1A (ACG1A), the known null phenotype in humans. TRIP11 encodes Golgi-associated microtubule-binding protein 210 (GMAP-210), an essential tether protein of the Golgi apparatus that physically interacts with intraflagellar transport 20 (IFT20), a component of the ciliary intraflagellar transport complex B. This association and extraskeletal disease manifestations in ODCD point to a cilium-dependent pathogenesis. However, our functional studies in patient-derived primary cells clearly support a Golgi-based disease mechanism. In spite of reduced abundance, residual GMAP variants maintain partial Golgi integrity, normal global protein secretion, and subcellular distribution of IFT20 in ODCD. These functions are lost when GMAP-210 is completely abrogated in ACG1A. However, a similar defect in chondrocyte maturation is observed in both disorders, which produces a cellular achondrogenesis phenotype of different severity, ensuing from aberrant glycan processing and impaired extracellular matrix proteoglycan secretion by the Golgi apparatus.

10.
Nat Med ; 25(4): 583-590, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30804514

RESUMO

MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression. Heterozygous loss-of-function point mutations of miRNA genes are associated with several human congenital disorders1-5, but neomorphic (gain-of-new-function) mutations in miRNAs due to nucleotide substitutions have not been reported. Here we describe a neomorphic seed region mutation in the chondrocyte-specific, super-enhancer-associated MIR140 gene encoding microRNA-140 (miR-140) in a novel autosomal dominant human skeletal dysplasia. Mice with the corresponding single nucleotide substitution show skeletal abnormalities similar to those of the patients but distinct from those of miR-140-null mice6. This mutant miRNA gene yields abundant mutant miR-140-5p expression without miRNA-processing defects. In chondrocytes, the mutation causes widespread derepression of wild-type miR-140-5p targets and repression of mutant miR-140-5p targets, indicating that the mutation produces both loss-of-function and gain-of-function effects. Furthermore, the mutant miR-140-5p seed competes with the conserved RNA-binding protein Ybx1 for overlapping binding sites. This finding may explain the potent target repression and robust in vivo effect by this mutant miRNA even in the absence of evolutionary selection of miRNA-target RNA interactions, which contributes to the strong regulatory effects of conserved miRNAs7,8. Our study presents the first case of a pathogenic gain-of-function miRNA mutation and provides molecular insight into neomorphic actions of emerging and/or mutant miRNAs.


Assuntos
Doenças do Desenvolvimento Ósseo/genética , Mutação com Ganho de Função/genética , MicroRNAs/genética , Animais , Sequência de Bases , Condrócitos/metabolismo , Feminino , Homozigoto , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Mutantes , MicroRNAs/metabolismo , Linhagem , Fenótipo , Transcriptoma/genética
11.
J Hum Genet ; 64(5): 467-471, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30796325

RESUMO

Spondylocarpotarsal synostosis syndrome, a rare syndromic skeletal disorder characterized by disrupted vertebral segmentation with vertebral fusion, scoliosis, short stature, and carpal/tarsal synostosis, has been associated with biallelic truncating mutations in the filamin B gene or monoallelic mutations in the myosin heavy chain 3 gene. We herein report the case of a patient with a typical phenotype of spondylocarpotarsal synostosis syndrome who had a homozygous frameshift mutation in the refilin A gene (RFLNA) [c.241delC, p.(Leu81Cysfs*111)], which encodes one of the filamin-binding proteins. Refilins, filamins, and myosins play critical roles in forming perinuclear actin caps, which change the nuclear morphology during cell migration and differentiation. The present study implies that RFLNA is an additional causative gene for spondylocarpotarsal synostosis syndrome in humans and a defect in forming actin bundles and perinuclear actin caps may be a critical mechanism for the development of spondylocarpotarsal synostosis syndrome.


Assuntos
Anormalidades Múltiplas/genética , Biomarcadores Tumorais/genética , Mutação da Fase de Leitura , Homozigoto , Vértebras Lombares/anormalidades , Doenças Musculoesqueléticas/genética , Escoliose/congênito , Sinostose/genética , Vértebras Torácicas/anormalidades , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/patologia , Biomarcadores Tumorais/metabolismo , Humanos , Lactente , Vértebras Lombares/metabolismo , Vértebras Lombares/patologia , Masculino , Doenças Musculoesqueléticas/metabolismo , Doenças Musculoesqueléticas/patologia , Escoliose/genética , Escoliose/metabolismo , Escoliose/patologia , Sinostose/metabolismo , Sinostose/patologia , Vértebras Torácicas/metabolismo , Vértebras Torácicas/patologia
12.
Eur J Med Genet ; 2019 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-30677517

RESUMO

Congenital insensitivity to pain with anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV (HSAN-IV), is a rare and severe autosomal recessive disorder. We report on an adult female patient whose clinical findings during childhood were not recognized as CIPA. There was neither complete anhidrosis nor a recognizable sensitivity to heat. Tumorlike swellings of many joints and skeletal signs of Charcot neuropathy developed in adolescence which, together with a history of self-mutilation, led to a clinical suspicion of CIPA confirmed by identification of a novel homozygous variant c.1795G > T in the NTRK1 gene in blood lymphocytes. Both parents were heterozygous for the mutation. The variant predicts a premature stop codon (p.Gly599Ter) and thus represents a pathogenic variant; the first reported in the Southeastern European population.

14.
Hum Mutat ; 2018 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-30488656

RESUMO

Spondyloepimetaphyseal dysplasias (SEMD) are a group of genetically heterogeneous skeletal disorders characterized by abnormal vertebral bodies and epimetaphyseal abnormalities. We investigated two families with a new SEMD type with one proband each. They showed mild facial dysmorphism, flat vertebral bodies (platyspondyly), large epiphyses, metaphyseal dysplasia, and hallux valgus as common clinical features. By trio-exome sequencing, the homozygous missense variant c.797G>A p.(Cys266Tyr) in PISD was found in both affected individuals. Based on exome data analyses for homozygous regions, the two patients shared a single homozygous block on chromosome 22 including PISD, indicating their remote consanguinity. PISD encodes phosphatidylserine decarboxylase that is localized in the inner mitochondrial membrane and catalyzes the decarboxylation of phosphatidylserine to phosphatidylethanolamine (PE) in mammalian cells. PE occurs at high abundance in mitochondrial membranes. Patient-derived fibroblasts showed fragmented mitochondrial morphology. Treatment of patient cells with MG-132 or staurosporine to induce activation of the intrinsic apoptosis pathway revealed significantly decreased cell viability with increased caspase-3 and -7 activation. Remarkably, ethanolamine supplementation largely restored cell viability and enhanced apoptosis in MG-132-stressed patient cells. Our data demonstrate that the bi-allelic hypomorphic PISD variant p.(Cys266Tyr) is associated with a novel SEMD form, which may be treatable with ethanolamine administration. This article is protected by copyright. All rights reserved.

15.
Am J Hum Genet ; 103(4): 553-567, 2018 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-30290151

RESUMO

The conserved oligomeric Golgi (COG) complex is involved in intracellular vesicular transport, and is composed of eight subunits distributed in two lobes, lobe A (COG1-4) and lobe B (COG5-8). We describe fourteen individuals with Saul-Wilson syndrome, a rare form of primordial dwarfism with characteristic facial and radiographic features. All affected subjects harbored heterozygous de novo variants in COG4, giving rise to the same recurrent amino acid substitution (p.Gly516Arg). Affected individuals' fibroblasts, whose COG4 mRNA and protein were not decreased, exhibited delayed anterograde vesicular trafficking from the ER to the Golgi and accelerated retrograde vesicular recycling from the Golgi to the ER. This altered steady-state equilibrium led to a decrease in Golgi volume, as well as morphologic abnormalities with collapse of the Golgi stacks. Despite these abnormalities of the Golgi apparatus, protein glycosylation in sera and fibroblasts from affected subjects was not notably altered, but decorin, a proteoglycan secreted into the extracellular matrix, showed altered Golgi-dependent glycosylation. In summary, we define a specific heterozygous COG4 substitution as the molecular basis of Saul-Wilson syndrome, a rare skeletal dysplasia distinct from biallelic COG4-CDG.

16.
J Hum Genet ; 63(12): 1277-1281, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30228365

RESUMO

Spondylocarpotarsal synostosis syndrome (SCT) is a rare group of skeletal dysplasias, characterized by disproportionate short stature with a short trunk, abnormal segmentation of the spine with vertebral fusion, scoliosis and lordosis, carpal and tarsal synostosis, and mild facial dysmorphisms. While the majority of the cases show autosomal recessive inheritance, only a few cases of vertical transmissions, with MYH3 mutations, have been reported. Here we report a case with typical SCT, carrying a novel heterozygous mutation in MYH3. This observation supports the hypothesis of a pathogenic link between autosomal dominant SCT and heterozygous mutations in MYH3. Of note, our case showed basilar invagination on brain magnetic resonance imaging at the age of 10 years. Basilar invagination could be a rare complication of both autosomal recessive and dominant SCT, indicating that prompt investigation are warranted for SCT patients.

17.
Hum Mutat ; 39(10): 1456-1467, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30080953

RESUMO

Skeletal dysplasias are a diverse group of rare Mendelian disorders with clinical and genetic heterogeneity. Here, we used targeted copy number variant (CNV) screening and identified intragenic exonic duplications, formed through Alu-Alu fusion events, in two individuals with skeletal dysplasia and negative exome sequencing results. First, we detected a homozygous tandem duplication of exon 9 and 10 in IFT81 in a boy with Jeune syndrome, or short-rib thoracic dysplasia (SRTD) (MIM# 208500). Western blot analysis did not detect any wild-type IFT81 protein in fibroblasts from the patient with the IFT81 duplication, but only a shorter isoform of IFT81 that was also present in the normal control samples. Complementary zebrafish studies suggested that loss of full-length IFT81 protein but expression of a shorter form of IFT81 protein affects the phenotype while being compatible with life. Second, a de novo tandem duplication of exons 2 to 5 in MATN3 was identified in a girl with multiple epiphyseal dysplasia (MED) type 5 (MIM# 607078). Our data highlights the importance of detection and careful characterization of intragenic duplication CNVs, presenting them as a novel and very rare genetic mechanism in IFT81-related Jeune syndrome and MATN3-related MED.

19.
J Pediatr Genet ; 7(3): 134-137, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30105123

RESUMO

Traditional approaches to prenatal genetic diagnosis for common presentations such as short femurs or intrauterine growth restriction are imperfect, and whole-exome sequencing is an emerging option. Mucolipidosis type II (I-cell disease) is an ultra-rare autosomal recessive lysosomal storage disorder with the potential for prenatal-onset skeletal and placental manifestations. We describe the prenatal signs in two recent unrelated patients with confirmed diagnoses soon after birth. In both cases, parents were consanguineous but there was no known family history of mucolipidosis type II. False reassurance was provided after negative testing for another disease with overlapping prenatal manifestations already present in one of the families, emphasizing that offspring of consanguineous parents can be at risk for more than one recessive condition. Our experience illustrates the potential advantages in expanding prenatal applications of WES for the identification of rare single gene disorders in offspring of consanguineous unions.

20.
Am J Med Genet A ; 176(9): 2009-2016, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30063090

RESUMO

Our understanding of the molecular basis of the genetic disorders of the skeleton has steadily increased, as the application of high-throughput sequencing technology has expanded. One of the newcomers is Spondyloepimetaphyseal dysplasia Faden-Alkuraya type. In this study, we aimed to further delineate the clinical, radiographic, and molecular findings of this entity in five affected individuals from two unrelated families. All patients have short stature, extremity deformities, facial dysmorphism and intellectual disability. The skeletal hallmarks include (a) mild spondylar dysplasia, (b) epimetaphyseal dysplasia of the long bones associated with coxa vara and genu valgum, (c) brachymesophalangy with cone-shaped epiphyses, and (d) craniosynostosis. Unlike the previously reported clinical findings, all patients except one are normocephalic, and all share the clinical findings including craniosynostosis, varying degrees of intellectual disability, facial dysmorphism, and skeletal findings including pes planus, prominent heels, and pectus deformity. Interestingly one of the patients presented with a cemento-ossifying fibrous lesion of the maxilla. Whole exome sequencing revealed a novel homozygous [c.377delT] [p.Ile126fs*] frameshift mutation at exon 2 in one family, while Sanger sequencing revealed a novel homozygous splice site mutation [c.516+2T>A] at exon 4/intron 4 border of RSPRY1 in the other family. In conclusion; we provide further evidence that Spondyloepimetaphyseal dysplasia Faden-Alkuraya type is a RSPRY1-associated skeletal dysplasia with a distinctive phenotype composed of spondyloepimetaphyseal dysplasia, cono-brachydactyly, and craniosynostosis along with recognizable facial features and intellectual disability.

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