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• W2020180377 abstract "Opsismodysplasia (OPS) is a severe autosomal-recessive chondrodysplasia characterized by pre- and postnatal micromelia with extremely short hands and feet. The main radiological features are severe platyspondyly, squared metacarpals, delayed skeletal ossification, and metaphyseal cupping. In order to identify mutations causing OPS, a total of 16 cases (7 terminated pregnancies and 9 postnatal cases) from 10 unrelated families were included in this study. We performed exome sequencing in three cases from three unrelated families and only one gene was found to harbor mutations in all three cases: inositol polyphosphate phosphatase-like 1 (INPPL1). Screening INPPL1 in the remaining cases identified a total of 12 distinct INPPL1 mutations in the 10 families, present at the homozygote state in 7 consanguinous families and at the compound heterozygote state in the 3 remaining families. Most mutations (6/12) resulted in premature stop codons, 2/12 were splice site, and 4/12 were missense mutations located in the catalytic domain, 5-phosphatase. INPPL1 belongs to the inositol-1,4,5-trisphosphate 5-phosphatase family, a family of signal-modulating enzymes that govern a plethora of cellular functions by regulating the levels of specific phosphoinositides. Our finding of INPPL1 mutations in OPS, a severe spondylodysplastic dysplasia with major growth plate disorganization, supports a key and specific role of this enzyme in endochondral ossification. Opsismodysplasia (OPS) is a severe autosomal-recessive chondrodysplasia characterized by pre- and postnatal micromelia with extremely short hands and feet. The main radiological features are severe platyspondyly, squared metacarpals, delayed skeletal ossification, and metaphyseal cupping. In order to identify mutations causing OPS, a total of 16 cases (7 terminated pregnancies and 9 postnatal cases) from 10 unrelated families were included in this study. We performed exome sequencing in three cases from three unrelated families and only one gene was found to harbor mutations in all three cases: inositol polyphosphate phosphatase-like 1 (INPPL1). Screening INPPL1 in the remaining cases identified a total of 12 distinct INPPL1 mutations in the 10 families, present at the homozygote state in 7 consanguinous families and at the compound heterozygote state in the 3 remaining families. Most mutations (6/12) resulted in premature stop codons, 2/12 were splice site, and 4/12 were missense mutations located in the catalytic domain, 5-phosphatase. INPPL1 belongs to the inositol-1,4,5-trisphosphate 5-phosphatase family, a family of signal-modulating enzymes that govern a plethora of cellular functions by regulating the levels of specific phosphoinositides. Our finding of INPPL1 mutations in OPS, a severe spondylodysplastic dysplasia with major growth plate disorganization, supports a key and specific role of this enzyme in endochondral ossification. Opsismodysplasia (OPS [MIM 258480]) is a rare chondrodysplasia, first described in 1977 by Zonana et al.1Zonana J. Rimoin D.L. Lachman R.S. Cohen A.H. A unique chondrodysplasia secondary to a defect in chondroosseous transformation.Birth Defects Orig. Artic. Ser. 1977; 13: 155-163PubMed Google Scholar and coined as “opsismodysplasia” (from “opsismos,” Greek for “late”) by Maroteaux et al. in 1984.2Maroteaux P. Stanescu V. Stanescu R. Four recently described osteochondrodysplasias.Prog. Clin. Biol. Res. 1982; 104: 345-350PubMed Google Scholar, 3Maroteaux P. Stanescu V. Stanescu R. Le Marec B. Moraine C. Lejarraga H. Opsismodysplasia: a new type of chondrodysplasia with predominant involvement of the bones of the hand and the vertebrae.Am. J. Med. Genet. 1984; 19: 171-182Crossref PubMed Scopus (32) Google Scholar To date, 30 cases have been reported and recurrence in sibs and/or consanguinity have suggested an autosomal-recessive mode of inheritance.4Cormier-Daire V. Delezoide A.L. Philip N. Marcorelles P. Casas K. Hillion Y. Faivre L. Rimoin D.L. Munnich A. Maroteaux P. Le Merrer M. Clinical, radiological, and chondro-osseous findings in opsismodysplasia: survey of a series of 12 unreported cases.J. Med. Genet. 2003; 40: 195-200Crossref PubMed Google Scholar The disorder is characterized by pre- and postnatal micromelia with extremely short hands and feet. The main radiological features are severe platyspondyly, squared metacarpals, major delay in skeletal ossification, and metaphyseal cupping. The outcome is more variable than initially thought, ranging from severe prenatal findings to late survival.4Cormier-Daire V. Delezoide A.L. Philip N. Marcorelles P. Casas K. Hillion Y. Faivre L. Rimoin D.L. Munnich A. Maroteaux P. Le Merrer M. Clinical, radiological, and chondro-osseous findings in opsismodysplasia: survey of a series of 12 unreported cases.J. Med. Genet. 2003; 40: 195-200Crossref PubMed Google Scholar In the international nosology for skeletal dysplasias,5Warman M.L. Cormier-Daire V. Hall C. Krakow D. Lachman R. LeMerrer M. Mortier G. Mundlos S. Nishimura G. Rimoin D.L. et al.Nosology and classification of genetic skeletal disorders: 2010 revision.Am. J. Med. Genet. A. 2011; 155A: 943-968Crossref PubMed Scopus (509) Google Scholar OPS belongs to the group of severe spondylodysplastic dysplasias (group 14). This group also includes (1) achondrogenesis type 1A (ACG1A [MIM 200600]) due to TRIPP11 mutations (MIM 604505) and distinct by poor ossification of vertebral bodies and skull, (2) Schneckenbecken dysplasia (MIM 296250) due to SLC35D1 mutations (MIM 610804) and characterized by a snail-like appearance of the ilia, (3) spondylometaphyseal dysplasia (SMD) Sedaghatian type (MIM 250220), a less severe condition, characterized by laciness of the iliac wings, and finally (4) fibrochondrogenesis (FCG [MIM 228520]), the molecular basis of which remains unknown. In order to identify the mutations causing OPS, a total of 16 cases from 10 unrelated families were included in this study. Among them, seven were terminated pregnancies (14–29 weeks of gestation) and nine were postnatal cases (birth to 19 years). Recurrency was observed in 5/10 families and consanguinity in 7/10. Inclusion criteria were (1) major delay in epiphyseal ossification, (2) platyspondyly, (3) metaphyseal cupping, and (4) very short metacarpals and phalanges (Figure 1). The clinical details are summarized in Table 1. Histological study of the femoral growth plate performed in the three cases from family 5 and in the prenatal case from family 3 (Table 1) showed similar disorganization of the growth plate with absence of columnar arrangement of proliferative cells and reduced hypertrophic zone with small number of hypertrophic chondrocytes (Figure 1A, III and IV). In two postnatal cases (Table 1, families 3 and 7), the phosphocalcic work up was normal (including blood levels of creatinine, calcium, phosphorus, thyroxin, thyrotropin, 25-hydroxyvitaminD, 1,25-dihydroxyvitaminD, parathyroid hormone, and urinary levels of creatinine, calcium, and phosphorus).Table 1Clinical Features of the Ten OPS FamiliesEthnic OriginCSPrenatal FindingsParameters at BirthFacial FeaturesRespiratory InsufficiencyShort Hand, FeetOtherOutcomeFamily 1, Sib 1Arab Moslem1st cousinshort long bones (25 WG)W 2,700 g; L 41.5 cm; HC 32.5 cmhypertelorism, high forehead, short nose, long philtrum, large fontanelle–yes–died at 15 monthsFamily 1, Sib 2Arab Moslem1st cousinshort long bones??–yes–termination of pregnancyFamily 2 (male)Somalianno??coarse face, hypertelorism, high forehead, short nose, large fontanellelung infectionsyes–4 years old; L, W ≤5 SD, HC P3Family 3, Sib 1 (male)French/Algeriannoureteral dilatationW 3,400 g; L 49 cm; HC 36 cmcoarse face, high forehead, short nose, long philtrum, large fontanelle–yesparaplegia after surgery for scoliosis19 years old; H 140 cm; W 36 kgFamily 3, Sib 2 (male)French/Algeriannopolyhydramnios, short femora (22 WG), narrow thorax, short hands, feetW 440 g; L 19.5 cm (22 WG)high forehead, short noselung hypoplasiayes–termination of pregnancy (22 WG)Family 4 (male)Portuguese1st cousinshort limbsW 3,300 g; L 45 cm; HC 38 cmhypertelorism, frontal bossing, short nose, long philtrum, macrostomia, wide fontanelleyes; narrow thoraxyescervical kyphosis, scoliosis19 yearsFamily 5, Sib 1 (male)Frenchnoshort limbs (24 WG), short hands, narrow thoraxW 1,280 g; L 33 cm; HC 29 cm (29 WG)coarse face, high forehead, short nose, long philtrumpulmonary hypoplasiayes–termination of pregnancy (29 WG)Family 5, Sib 2 (female)Frenchnohygroma, short limbs (14 WG), narrow thoraxW 30 g; L 9.5 cm (15 WG)––––termination of pregnancy (15 WG)Family 5, Sib 3 (female)Frenchnohygroma, narrow thorax, short limbsW 40 g; L 8.5 cm (14 WG)––––termination of pregnancy (14 WG)Family 6 (male)Arab (Saudi)1st cousinshort limbs?hypertelorism, midface hypoplasia, wide fontanelle, broad foreheadchronic lung diseaseyestricuspide and mitral valve prolapse3.5 years oldFamily 7 (male)Algerian2nd cousin–W 3120 g; L 34 cm; HC 34 cmhigh forehead, short nose with anteverted nares–yesscoliosis, lower limb varus deformity9 years old; H 115 cm (≤4 SD); W 24.9 kg; HC 55.5 cmFamily 8, Sib 1 (female)Frenchnoshort femora (24 W), short hands, narrow thoraxW 1,400 g; L 29 cm; HC 31 cmcoarse face, high forehead, short nosepulmonary hypoplasiayes–termination of pregnancy (29 WG)Family 8, Sib2 (female)Frenchnohygroma, IUGRL 9 cm (15 WG)––yes–termination of pregnancy (15 WG)Family 9 (male)Brazil1st cousinshort limbs, polyhydramniosW 1,455 g; L 32 cm; HC 29 cmbrachycephaly, midface hypoplasia, broad forehead, short nose, long philtrum, retrognathia, low-set earspulmonary hypoplasiayesshort neck, narrow thorax, prominent calcaneusstillborn (30 WG)Family 10, Sib 1 (male)Brazil7th cousinshort limbs, narrow thorax, polyhydramniosW 2,620 g; L 40 cm; (35 WG)brachycephaly, midface hypoplasia, broad forehead, short nose, low-set earsyesyesabsence right kidney (prenatal US)died at 5 daysFamily 10, Sib 2Brazil7th cousinshort limbs, narrow thorax, platspondylyW 2,420 g; L 35.5 cm; HC 36 cm (36 WG)brachycephaly, midface hypoplasia, broad forehead, short nose, low-set earsyesyes–died at 30 minAbbreviations are as follows: CS, consanguinity; WG, weeks of gestation; L, length; W, weight; HC, head circumference; IUGR, intrauterine growth retardation; ?, unknown; –, no.Families 3–5 have been previously published in Cormier-Daire et al.4Cormier-Daire V. Delezoide A.L. Philip N. Marcorelles P. Casas K. Hillion Y. Faivre L. Rimoin D.L. Munnich A. Maroteaux P. Le Merrer M. Clinical, radiological, and chondro-osseous findings in opsismodysplasia: survey of a series of 12 unreported cases.J. Med. Genet. 2003; 40: 195-200Crossref PubMed Google Scholar and family 4 was previously published in Santos et al.17Santos H.G. Saraiva J.M. Opsismodysplasia: another case and literature review.Clin. Dysmorphol. 1995; 4: 222-226PubMed Google Scholar Open table in a new tab Abbreviations are as follows: CS, consanguinity; WG, weeks of gestation; L, length; W, weight; HC, head circumference; IUGR, intrauterine growth retardation; ?, unknown; –, no. Families 3–5 have been previously published in Cormier-Daire et al.4Cormier-Daire V. Delezoide A.L. Philip N. Marcorelles P. Casas K. Hillion Y. Faivre L. Rimoin D.L. Munnich A. Maroteaux P. Le Merrer M. Clinical, radiological, and chondro-osseous findings in opsismodysplasia: survey of a series of 12 unreported cases.J. Med. Genet. 2003; 40: 195-200Crossref PubMed Google Scholar and family 4 was previously published in Santos et al.17Santos H.G. Saraiva J.M. Opsismodysplasia: another case and literature review.Clin. Dysmorphol. 1995; 4: 222-226PubMed Google Scholar Informed consent for participation and sample collection were obtained by protocols approved by the Necker Hospital ethics board committee. We first excluded the genes involved in the lethal spondylodysplastic group by direct sequencing, namely SBDS (MIM 607444) involved in some cases of spondylometaphyseal dysplasia Sedhagatian type,6Boocock G.R.B. Morrison J.A. Popovic M. Richards N. Ellis L. Durie P.R. Rommens J.M. Mutations in SBDS are associated with Shwachman-Diamond syndrome.Nat. Genet. 2003; 33: 97-101Crossref PubMed Scopus (549) Google Scholar SLC35D1,7Hiraoka S. Furuichi T. Nishimura G. Shibata S. Yanagishita M. Rimoin D.L. Superti-Furga A. Nikkels P.G. Ogawa M. Katsuyama K. et al.Nucleotide-sugar transporter SLC35D1 is critical to chondroitin sulfate synthesis in cartilage and skeletal development in mouse and human.Nat. Med. 2007; 13: 1363-1367Crossref PubMed Scopus (93) Google Scholar and TRIP11.8Smits P. Bolton A.D. Funari V. Hong M. Boyden E.D. Lu L. Manning D.K. Dwyer N.D. Moran J.L. Prysak M. et al.Lethal skeletal dysplasia in mice and humans lacking the golgin GMAP-210.N. Engl. J. Med. 2010; 362: 206-216Crossref PubMed Scopus (107) Google Scholar We then decided to undertake an exome capture-sequencing in three OPS cases from families 1–3. Exome capture was performed at the French National Sequencing Institute (CNG) with the SureSelect Human All Exon kit (Agilent Technologies).9Byun M. Abhyankar A. Lelarge V. Plancoulaine S. Palanduz A. Telhan L. Boisson B. Picard C. Dewell S. Zhao C. et al.Whole-exome sequencing-based discovery of STIM1 deficiency in a child with fatal classic Kaposi sarcoma.J. Exp. Med. 2010; 207: 2307-2312Crossref PubMed Scopus (226) Google Scholar Single-end sequencing was performed on an Illumina Genome Analyzer IIx (Illumina), generating 72-base reads. For sequence alignment, variant calling, and annotation, the sequences were aligned to the human genome reference sequence (hg18 build), via BWA aligner.10Li H. Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform.Bioinformatics. 2009; 25: 1754-1760Crossref PubMed Scopus (26648) Google Scholar Downstream processing was carried out with the Genome Analysis Toolkit (GATK),11McKenna A. Hanna M. Banks E. Sivachenko A. Cibulskis K. Kernytsky A. Garimella K. Altshuler D. Gabriel S. Daly M. DePristo M.A. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data.Genome Res. 2010; 20: 1297-1303Crossref PubMed Scopus (14776) Google Scholar SAMtools,12Li H. Handsaker B. Wysoker A. Fennell T. Ruan J. Homer N. Marth G. Abecasis G. Durbin R. 1000 Genome Project Data Processing SubgroupThe Sequence Alignment/Map format and SAMtools.Bioinformatics. 2009; 25: 2078-2079Crossref PubMed Scopus (31559) Google Scholar and Picard Tools. Substitution calls were made with GATK Unified Genotyper, whereas indel calls were made with a GATK IndelGenotyperV2. All calls with a read coverage ≤2× and a Phred-scaled SNP quality of ≤20 were filtered out. All the variants were annotated with an in-house developed annotation software system. We first focused our analyses on nonsynonymous variants, splice acceptor and donor site mutations, and coding indels, anticipating that synonymous variants were far less likely to be disease causing (Table S1 available online). We also defined variants as previously unidentified if they were absent from both control populations and data sets including dbSNP129, the 1000 Genomes Project, and in-house exome data. Based on the recessive mode of inheritance of OPS, only one gene was found to harbor mutations in all three cases (Table S1) and was therefore selected. This gene, inositol polyphosphate phosphatase-like 1 (INPPL1), is also referred to as SHIP2, for SH2 (Src homology 2)-domain-containing inositol phosphatase (MIM 600829). Indeed, exome analysis detected five INPPL1 mutations in the three individuals and was present at the homozygote state in case 1 and compound heterozygote state in cases 2 and 3. These results were confirmed by Sanger sequencing. INPPL1 (RefSeq accession number NM_001567.3) is composed of 28 coding exons and encodes a protein of 1,258 amino acids characterized by a N-terminal SH2 domain, a conserved catalytic 5-phosphatase domain, a C-terminal proline-rich region with consensus sites for SH3 domain interactions, a ubiquitin interacting motif, and a sterile alpha motif (SAM) (Figure 2). Subsequent screening of the 28 INPPL1 coding exons in the remaining cases led to identification of seven additional mutations. Altogether, we identified a total of 12 distinct INPPL1 mutations in the 10 families (Figure 2, Table 2). Among them, 2/12 were nonsense mutations (c.2845C>T [p.Arg949∗], c.2719C>T [p.Arg907∗]) and 4/12 were frameshift mutations (c.276_280del [p.Gln93Profs∗3], c.1845dupT [p.Ile616Tyrfs∗14], c.94_121del [p.Glu32Metfs∗77], c.1328delinsTA [p.Thr443Ilefs∗23]) located in regions encoding the SH3 binding, SH2, or 5-phosphatase domains. They were expected to result in a truncated protein with no prolin-rich and SAM domains, which are crucial for protein-protein interaction. In addition, 2/12 were splice-site mutations (c.519−3A>G, c.1951+1G>A). Alamut Splicing Predictions, via bioinformatic analysis SSF, MaxEnt, NNSPLICE, and HSF, predicted a new acceptor site in c.519−2, generating a frameshift of two additional bases followed by a premature stop codon, and the suppression of the donor site in c.1951, generating a premature stop codon. Finally, 4/12 were missense mutations (c.1975C>T [p.Pro659Ser], c.1201C>T [p.Arg401Trp], c.2164T>A [p.Phe722Ile], c.2064G>T [p.Trp688Lys]) located in the 5-phosphatase domain. These mutations cosegregated with the disease, were present at the heterozygote state in the parents, were considered as pathogenic in the PolyPhen and Sift database, and were absent from alleles in 200 ethnicity-matched controls.Table 2INPPL1 Mutations in Families in OpsismodyplasiaFamilyEthnic OriginCSNo. of Affected ChildrenNucleotide ChangeStatusAmino Acid ChangeLocationDomain1Arab Moslemyes2c.2845C>T/hop.Arg949∗Ex25SH3 binding domain2Somalianno1c.276_280delhep.Gln93Profs∗3Ex3SH2 domainc.1975C>Thep.Pro659SerEx175phophatase domain3French/Algerianno2c.1201C>Thep.Arg401TrpEx115phophatase domainc.2164T>Ahep.Phe722IleEx195phophatase domain4Portugueseyes1c.2719C>Thop.Arg907∗Ex24/5Frenchyes3c.1845dupThop.Ile616Tyrfs∗14Ex155phophatase domain6Arab (Saudi)yes1c.519-3A>Gho?In4/7Algerianyes1c.1951+1G>Aho?In16/8Frenchno2c.1328delinsTAc.2064G>Thehep.Thr443Ilefs∗23p.Trp688LysEx12Ex185phophatase domain 5phophatase domain9Brazilyes1c.94_121delhop.Glu32Metfs∗77Ex1SH2 domain10Brazilyes2c.94_121delhop.Glu32Metfs∗77Ex1SH2 domainAbbreviations are as follows: Cs, consanguinity; ho, homozygote; he, heterozygote; /, mutation not localized in a known protein domain. Open table in a new tab Abbreviations are as follows: Cs, consanguinity; ho, homozygote; he, heterozygote; /, mutation not localized in a known protein domain. Here, we report INPPL1 mutations in ten unrelated families of opsismodysplasia. All cases clearly fulfilled the diagnostic criteria for OPS but were variable in severity. Indeed, prenatal findings detected in four families led to early termination of pregnancies (especially in recurrent sibs) in 7/16 cases and hygroma, short long bones, short extremities, and narrow thorax were consistently observed. Four children died early (stillborn at 30 weeks of gestation to 15 months of age). The five remaining cases ranged in age from 3 to 19 years old and had normal cognitive development, severe short stature (<4 SDS), lower limb deformity, and severe scoliosis with atlanto axial instability (at least in one case). Most mutations (6/12) resulted in premature stop codons, 2/12 were splice-site mutations, and 4/12 were missense mutations located in the catalytic domain, 5-phosphatase, presumably responsible for impaired catalytic activity. INPPL1 belongs to the inositol-1,4,5-trisphosphate 5-phosphatase family, a family of signal-modulating enzymes that govern a plethora of cellular functions by regulating the levels of specific phosphoinositides. Growth factor or insulin stimulation induces a canonical cascade resulting in the transient phosphorylation of phosphatidylinositol (PtdIns) (4,5)P(2) by PI3K (phosphoinositide 3-kinase) to form PtdIns(3,4,5)P(3), which is rapidly dephosphorylated either by phosphatase and tensin homolog (PTEN) back to PtdIns(4,5)P(2) or by the inositol polyphosphate 5-phosphatases (5-ptases) generating PtdIns(3,4)P(2). Ten mammalian 5-ptases have been identified. Their gene-targeted deletion in mice has revealed that these enzymes regulate haemopoietic cell proliferation, synaptic vesicle recycling, insulin signaling, endocytosis, vesicular trafficking, and actin polymerization.13Ooms L.M. Horan K.A. Rahman P. Seaton G. Gurung R. Kethesparan D.S. Mitchell C.A. The role of the inositol polyphosphate 5-phosphatases in cellular function and human disease.Biochem. J. 2009; 419: 29-49Crossref PubMed Scopus (178) Google Scholar More specifically, INPPL1 has been implicated in the negative regulation of insulin signaling and glucose homeostasis in specific tissues.14Dyson J.M. Kong A.M. Wiradjaja F. Astle M.V. Gurung R. Mitchell C.A. The SH2 domain containing inositol polyphosphate 5-phosphatase-2: SHIP2.Int. J. Biochem. Cell Biol. 2005; 37: 2260-2265Crossref PubMed Scopus (50) Google Scholar SNP analysis in the Japanese population have suggested that INPPL1 polymorphisms are associated with a predisposition to insulin resistance.15Kagawa S. Sasaoka T. Yaguchi S. Ishihara H. Tsuneki H. Murakami S. Fukui K. Wada T. Kobayashi S. Kimura I. Kobayashi M. Impact of SRC homology 2-containing inositol 5′-phosphatase 2 gene polymorphisms detected in a Japanese population on insulin signaling.J. Clin. Endocrinol. Metab. 2005; 90: 2911-2919Crossref PubMed Scopus (51) Google Scholar Moreover, animal models lacking Inppl1 had increased glucose intolerance and insulin sensitivity. However, Inppl1−/− mice were viable and had normal glucose and insulin levels but were highly resistant to weight gain, suggesting that Inppl1 mediates obesity resistance.16Sleeman M.W. Wortley K.E. Lai K.-M.V. Gowen L.C. Kintner J. Kline W.O. Garcia K. Stitt T.N. Yancopoulos G.D. Wiegand S.J. Glass D.J. Absence of the lipid phosphatase SHIP2 confers resistance to dietary obesity.Nat. Med. 2005; 11: 199-205Crossref PubMed Scopus (201) Google Scholar In the four survivors from our series, no insulin resistance was reported and length and weight were both ≤4 SD. Recent studies have suggested additional noncatalytic properties of INPPL1 that may act as a docking protein for a large number of proteins including cytoskeletal, focal adhesion, or scaffold proteins, phosphatases, and tyrosine kinase-associated receptors, like EGF receptor. Moreover, loss of INPPL1 in zebrafish led to an increased and expanded expression of outputs of FGF-mediated signaling.13Ooms L.M. Horan K.A. Rahman P. Seaton G. Gurung R. Kethesparan D.S. Mitchell C.A. The role of the inositol polyphosphate 5-phosphatases in cellular function and human disease.Biochem. J. 2009; 419: 29-49Crossref PubMed Scopus (178) Google Scholar The finding of INPPL1 mutations in OPS, a severe spondylodysplastic dysplasia with major growth plate disorganization, supports a key and specific role of this enzyme in the endochondral ossification process, through either its role in postranslational modifications (phosphorylation or ubiquitination) or its interaction with specific protein network. We conclude that INPPL1 mutations are responsible for OPS. Ongoing studies will hopefully lead to an understanding of the specific role of this enzyme in the ossification process. We thank all families for their contribution to this work. We thank the GIS Maladies Rares for the funding of the exome project. Download .pdf (.01 MB) Help with pdf files Document S1. Table S1 The URLs for data presented herein are as follows:Alamut, http://www.interactive-biosoftware.com/Online Mendelian Inheritance in Man (OMIM), http://www.omim.org/Pfam, http://pfam.sanger.ac.uk/Picard, http://picard.sourceforge.net/Polyphen, http://genetics.bwh.harvard.edu/pph/index.htmlRefSeq, http://www.ncbi.nlm.nih.gov/RefSeqSIFT, http://sift.bii.a-star.edu.sg/UniProt, http://www.uniprot.org/ Whole-Genome Analysis Reveals that Mutations in Inositol Polyphosphate Phosphatase-like 1 Cause OpsismodysplasiaBelow et al.The American Journal of Human GeneticsDecember 27, 2012In BriefOpsismodysplasia is a rare, autosomal-recessive skeletal dysplasia characterized by short stature, characteristic facial features, and in some cases severe renal phosphate wasting. We used linkage analysis and whole-genome sequencing of a consanguineous trio to discover that mutations in inositol polyphosphate phosphatase-like 1 (INPPL1) cause opsismodysplasia with or without renal phosphate wasting. Evaluation of 12 families with opsismodysplasia revealed that INPPL1 mutations explain ∼60% of cases overall, including both of the families in our cohort with more than one affected child and 50% of the simplex cases. Full-Text PDF Open Archive" @default.
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• W2020180377 title "Exome Sequencing Identifies INPPL1 Mutations as a Cause of Opsismodysplasia" @default.
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