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• W2003994376 abstract "Catel-Manzke syndrome is characterized by Pierre Robin sequence and a unique form of bilateral hyperphalangy causing a clinodactyly of the index finger. We describe the identification of homozygous and compound heterozygous mutations in TGDS in seven unrelated individuals with typical Catel-Manzke syndrome by exome sequencing. Six different TGDS mutations were detected: c.892A>G (p.Asn298Asp), c.270_271del (p.Lys91Asnfs∗22), c.298G>T (p.Ala100Ser), c.294T>G (p.Phe98Leu), c.269A>G (p.Glu90Gly), and c.700T>C (p.Tyr234His), all predicted to be disease causing. By using haplotype reconstruction we showed that the mutation c.298G>T is probably a founder mutation. Due to the spectrum of the amino acid changes, we suggest that loss of function in TGDS is the underlying mechanism of Catel-Manzke syndrome. TGDS (dTDP-D-glucose 4,6-dehydrogenase) is a conserved protein belonging to the SDR family and probably plays a role in nucleotide sugar metabolism. Catel-Manzke syndrome is characterized by Pierre Robin sequence and a unique form of bilateral hyperphalangy causing a clinodactyly of the index finger. We describe the identification of homozygous and compound heterozygous mutations in TGDS in seven unrelated individuals with typical Catel-Manzke syndrome by exome sequencing. Six different TGDS mutations were detected: c.892A>G (p.Asn298Asp), c.270_271del (p.Lys91Asnfs∗22), c.298G>T (p.Ala100Ser), c.294T>G (p.Phe98Leu), c.269A>G (p.Glu90Gly), and c.700T>C (p.Tyr234His), all predicted to be disease causing. By using haplotype reconstruction we showed that the mutation c.298G>T is probably a founder mutation. Due to the spectrum of the amino acid changes, we suggest that loss of function in TGDS is the underlying mechanism of Catel-Manzke syndrome. TGDS (dTDP-D-glucose 4,6-dehydrogenase) is a conserved protein belonging to the SDR family and probably plays a role in nucleotide sugar metabolism. Catel-Manzke syndrome (MIM 302380) is characterized by Pierre Robin sequence (MIM 261800; HP:0000201)1Robinson P.N. Köhler S. Bauer S. Seelow D. Horn D. Mundlos S. The Human Phenotype Ontology: a tool for annotating and analyzing human hereditary disease.Am. J. Hum. Genet. 2008; 83: 610-615Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar and a unique form of bilateral hyperphalangy causing clinodactyly of the index finger (HP:0009467). The condition was first described by Catel2Catel W. Differentialdiagnose von Krankheitssymptomen bei Kindern und Jugendlichen. G. Thieme, Stuttgart1961Google Scholar in 1961 and Manzke3Manzke H. [Symmetrical hyperphalangy of the second finger by a supplementary metacarpus bone].Fortschr. Geb. Rontgenstr. Nuklearmed. 1966; 105: 425-427Crossref PubMed Google Scholar in 1966. Pierre Robin sequence is defined by micrognathia, obstruction of the airways due to a backward displacement of the tongue base, and, often but not always, cleft palate.4Sheffield L.J. Reiss J.A. Strohm K. Gilding M. A genetic follow-up study of 64 patients with the Pierre Robin complex.Am. J. Med. Genet. 1987; 28: 25-36Crossref PubMed Scopus (65) Google Scholar The bilateral clinodactyly is caused by an accessory bone between the second metacarpal and its corresponding proximal phalanx, resulting in radial deviation of the index finger.5Manzke H. Lehmann K. Klopocki E. Caliebe A. Catel-Manzke syndrome: two new patients and a critical review of the literature.Eur. J. Med. Genet. 2008; 51: 452-465Crossref PubMed Scopus (29) Google Scholar This is sometimes referred to as Manzke dysostosis. Because not all reported cases have a cleft palate, Manzke suggested replacing the term palatodigital syndrome by the term micrognathia-digital syndrome.5Manzke H. Lehmann K. Klopocki E. Caliebe A. Catel-Manzke syndrome: two new patients and a critical review of the literature.Eur. J. Med. Genet. 2008; 51: 452-465Crossref PubMed Scopus (29) Google Scholar Previously, 26 individuals from 24 families with typical Catel-Manzke syndrome have been reported2Catel W. Differentialdiagnose von Krankheitssymptomen bei Kindern und Jugendlichen. G. Thieme, Stuttgart1961Google Scholar, 3Manzke H. [Symmetrical hyperphalangy of the second finger by a supplementary metacarpus bone].Fortschr. Geb. Rontgenstr. Nuklearmed. 1966; 105: 425-427Crossref PubMed Google Scholar, 6Farnsworth P.B. Pacik P.T. Glossoptotic hypoxia and micrognathia—the Pierre Robin syndrome reviewed. Early recognition and prompt surgical treatment is important for survival.Clin. Pediatr. (Phila.). 1971; 10: 600-606Crossref PubMed Scopus (15) Google Scholar, 7Gorlin R.J. Cervenka J. Pruzansky S. Facial clefting and its syndromes.Birth Defects Orig. Artic. Ser. 1971; 7: 3-49PubMed Google Scholar, 8Holthusen W. [The Pierre Robin syndrome: unusual associated developmental defects].Ann. Radiol. (Paris). 1972; 15: 253-262PubMed Google Scholar, 9Silengo M.C. Franceschini P. Cerutti A. Fabris C. Pierre Robin syndrome with hyperphalangism-clinodactylysm of the index finger: a possible new palato-digital syndrome.Pediatr. Radiol. 1977; 6: 178-180Crossref PubMed Scopus (11) Google Scholar, 10Gewitz M. Dinwiddie R. Yuille T. Hill F. Carter C.O. Cleft palate and accessory metacarpal of index finger syndrome: possible familial occurrence.J. Med. Genet. 1978; 15: 162-164Crossref PubMed Scopus (15) Google Scholar, 11Klug M.S. Ketchum L.D. Lipsey J.H. Symmetric hyperphalangism of the index finger in the palatodigital syndrome: a case report.J. Hand Surg. Am. 1983; 8: 599-603Abstract Full Text PDF PubMed Scopus (7) Google Scholar, 12Brude E. Pierre Robin sequence and hyperphalangy—a genetic entity (Catel-Manzke syndrome).Eur. J. Pediatr. 1984; 142: 222-223Crossref PubMed Scopus (16) Google Scholar, 13Thompson E.M. Winter R.M. Williams M.J. A male infant with the Catel-Manzke syndrome and dislocatable knees.J. Med. Genet. 1986; 23: 271-274Crossref PubMed Scopus (15) Google Scholar, 14Dignan P.S. Martin L.W. Zenni Jr., E.J. Pierre Robin anomaly with an accessory metacarpal of the index fingers. The Catel-Manzke syndrome.Clin. Genet. 1986; 29: 168-173Crossref PubMed Scopus (13) Google Scholar, 15Skinner Sr., S.A. Flannery D.B. Catel-Manzke Syndrome.Proc. Greenwood Genetic Center. 1989; 8: 60-63Google Scholar, 16Bernd L. Martini A.K. Schiltenwolf M. Graf J. [Hyperphalangia in Pierre-Robin syndrome].Z. Orthop. Ihre Grenzgeb. 1990; 128: 463-465Crossref PubMed Scopus (3) Google Scholar, 17Buck-Gramcko D. Congenital Malformations of the Hand and Forearm. Chuchvill Livingstone, London1998Google Scholar, 18Kant S.G. Oudshoorn A. Gi C.V. Zonderland H.M. Van Haeringen A. The Catel-Manzke syndrome in a female infant.Genet. Couns. 1998; 9: 187-190PubMed Google Scholar, 19Puri R.D. Phadke S.R. Catel-Manzke syndrome without cleft palate: a case report.Clin. Dysmorphol. 2003; 12: 279-281Crossref PubMed Scopus (8) Google Scholar, 20Nizon M. Alanay Y. Tuysuz B. Kiper P.O. Geneviève D. Sillence D. Huber C. Munnich A. Cormier-Daire V. IMPAD1 mutations in two Catel-Manzke like patients.Am. J. Med. Genet. A. 2012; 158A: 2183-2187Crossref PubMed Scopus (26) Google Scholar, 21Kiraz A. Tubas F. Ekinci Y. Dögen M.E. Varli M. A patient with hyperphalangism: the milder phenotype of Catel-Manzke syndrome.Clin. Dysmorphol. 2013; 22: 169-171Crossref PubMed Scopus (2) Google Scholar, 22Gorlin R.J. Cohen M.M. Hennekam R.C.M. Syndromes of the Head and Neck. Oxford University Press, Oxford2001Google Scholar, 23Kapoor S. Ghosh V. Dhua A. Aggarwal S.K. Cystic hygroma and hirsutism in a child with Catel-Manzke syndrome.Clin. Dysmorphol. 2011; 20: 117-120Crossref PubMed Scopus (6) Google Scholar (reviewed by Manzke et al.5Manzke H. Lehmann K. Klopocki E. Caliebe A. Catel-Manzke syndrome: two new patients and a critical review of the literature.Eur. J. Med. Genet. 2008; 51: 452-465Crossref PubMed Scopus (29) Google Scholar). Ten cases of an atypical form of Catel-Manzke syndrome have been described, including individuals with an extended phenotype20Nizon M. Alanay Y. Tuysuz B. Kiper P.O. Geneviève D. Sillence D. Huber C. Munnich A. Cormier-Daire V. IMPAD1 mutations in two Catel-Manzke like patients.Am. J. Med. Genet. A. 2012; 158A: 2183-2187Crossref PubMed Scopus (26) Google Scholar, 24Stevenson R.E. Taylor Jr., H.A. Burton O.M. Hearn 3rd, H.B. A digitopalatal syndrome with associated anomalies of the heart, face, and skeleton.J. Med. Genet. 1980; 17: 238-242Crossref PubMed Scopus (19) Google Scholar, 25Sundaram V. Taysi K. Hartmann Jr., A.F. Shackelford G.D. Keating J.P. Hyperphalangy and clinodactyly of the index finger with Pierre Robin anomaly: Catel-Manzke syndrome. A case report and review of the literature.Clin. Genet. 1982; 21: 407-410Crossref PubMed Scopus (17) Google Scholar, 26Wilson G.N. King T.E. Brookshire G.S. Index finger hyperphalangy and multiple anomalies: Catel-Manzke syndrome?.Am. J. Med. Genet. 1993; 46: 176-179Crossref PubMed Scopus (16) Google Scholar, 27Clarkson J.H. Homfray T. Heron C.W. Moss A.L. Catel-Manzke syndrome: a case report of a female with severely malformed hands and feet. An extension of the phenotype or a new syndrome?.Clin. Dysmorphol. 2004; 13: 237-240Crossref PubMed Scopus (9) Google Scholar, 28Kiper P.O. Utine G.E. Boduroğlu K. Alanay Y. Catel-Manzke syndrome: a clinical report suggesting autosomal recessive inheritance.Am. J. Med. Genet. A. 2011; 155A: 2288-2292Crossref PubMed Scopus (7) Google Scholar and case subjects with unilateral hyperphalangism.15Skinner Sr., S.A. Flannery D.B. Catel-Manzke Syndrome.Proc. Greenwood Genetic Center. 1989; 8: 60-63Google Scholar, 29Oh S.H. Park K.E. Park Y.B. Yang Jr., S.K. A case of Catel Manzke syndrome.J. Korean Pediatr. Soc. 1999; 42: 1154-1158Google Scholar, 30Lipson A. Beuhler B. Bartley J. Walsh D. Yu J. O’Halloran M. Webster W. Maternal hyperphenylalaninemia fetal effects.J. Pediatr. 1984; 104: 216-220Abstract Full Text PDF PubMed Scopus (64) Google Scholar Additionally, two cases of Manzke dysostosis without Pierre Robin sequence have been reported.17Buck-Gramcko D. Congenital Malformations of the Hand and Forearm. Chuchvill Livingstone, London1998Google Scholar, 31Dudin A. Abdelshafi M. Rambaud-Cousson A. Choledochal cyst associated with rare hand malformation.Am. J. Med. Genet. 1995; 56: 161-163Crossref PubMed Scopus (9) Google Scholar In one family two affected girls and in a second family two affected boys were observed.12Brude E. Pierre Robin sequence and hyperphalangy—a genetic entity (Catel-Manzke syndrome).Eur. J. Pediatr. 1984; 142: 222-223Crossref PubMed Scopus (16) Google Scholar, 14Dignan P.S. Martin L.W. Zenni Jr., E.J. Pierre Robin anomaly with an accessory metacarpal of the index fingers. The Catel-Manzke syndrome.Clin. Genet. 1986; 29: 168-173Crossref PubMed Scopus (13) Google Scholar The latter observations and parental consanguinity in another family20Nizon M. Alanay Y. Tuysuz B. Kiper P.O. Geneviève D. Sillence D. Huber C. Munnich A. Cormier-Daire V. IMPAD1 mutations in two Catel-Manzke like patients.Am. J. Med. Genet. A. 2012; 158A: 2183-2187Crossref PubMed Scopus (26) Google Scholar indicate autosomal-recessive inheritance. We identified homozygous and compound heterozygous mutations in TGDS in seven unrelated individuals with typical Catel-Manzke syndrome by using exome sequencing. Clinical data and mutations are summarized in Table 1.Table 1TGDS Mutations and Clinical Presentation of the Seven Analyzed Individuals with Typical Catel-Manzke SyndromeIndividual 1Individual 2Individual 35Manzke H. Lehmann K. Klopocki E. Caliebe A. Catel-Manzke syndrome: two new patients and a critical review of the literature.Eur. J. Med. Genet. 2008; 51: 452-465Crossref PubMed Scopus (29) Google ScholarIndividual 45Manzke H. Lehmann K. Klopocki E. Caliebe A. Catel-Manzke syndrome: two new patients and a critical review of the literature.Eur. J. Med. Genet. 2008; 51: 452-465Crossref PubMed Scopus (29) Google ScholarIndividual 52Catel W. Differentialdiagnose von Krankheitssymptomen bei Kindern und Jugendlichen. G. Thieme, Stuttgart1961Google Scholar, 3Manzke H. [Symmetrical hyperphalangy of the second finger by a supplementary metacarpus bone].Fortschr. Geb. Rontgenstr. Nuklearmed. 1966; 105: 425-427Crossref PubMed Google Scholar, 5Manzke H. Lehmann K. Klopocki E. Caliebe A. Catel-Manzke syndrome: two new patients and a critical review of the literature.Eur. J. Med. Genet. 2008; 51: 452-465Crossref PubMed Scopus (29) Google ScholarIndividual 618Kant S.G. Oudshoorn A. Gi C.V. Zonderland H.M. Van Haeringen A. The Catel-Manzke syndrome in a female infant.Genet. Couns. 1998; 9: 187-190PubMed Google ScholarIndividual 720Nizon M. Alanay Y. Tuysuz B. Kiper P.O. Geneviève D. Sillence D. Huber C. Munnich A. Cormier-Daire V. IMPAD1 mutations in two Catel-Manzke like patients.Am. J. Med. Genet. A. 2012; 158A: 2183-2187Crossref PubMed Scopus (26) Google ScholarSexmalefemalefemalefemalemalefemalefemaleConsanguinitynonenonenonenonenonenonenoneEthnicityCameroonBritish/ South AmericanGermanGermanGermanDutchFrenchAge at last exam18 months3.5 years16 months19 years52 years17 years28 yearsMutation1st mutationc.892A>G (p.Asn298Asp)c.298G>T (p.Ala100Ser)c.298G>T (p.Ala100Ser)c.298G>T (p.Ala100Ser)c.298G>T (p.Ala100Ser)c.298G>T (p.Ala100Ser)c.298G>T (p.Ala100Ser)2nd mutationc.270_271del (p.Lys91Asnfs∗22)c.294T>G (p.Phe98Leu)–––c.700T>C (p.Tyr234His)c.269A>G (p.Glu90Gly)Typecompound heterozygouscompound heterozygoushomozygoushomozygoushomozygouscompound heterozygouscompound heterozygousClinical ManifestationsPierre Robin sequence+++++++Cleft palate+, V-shaped+, U-shaped+, U-shaped++, U-shapedhigh arched palate, bifid uvula+, U-shapedManzke dysostosis+++++++Joint hypermobilitynrnrnrnrnr++Congenital heart defect–VSD, spontaneous closure–––VSD–Facial dysmorphism (additional to micrognathia)low-set ears, prominent antheliceshypertelorism, upslanted palpebral fissures, thin eyebrowsnarrow nostrils, thin arched eyebrows, full cheeks, hypertelorismmild hypertelorism, narrow nosenrthin eyebrows, mild proptosis, long columella, low-set ears, dysplastic helices, small mouthnrOther skeletal anomaliesshort toes, short humeri, short femoranrnrclinodactyly V, genua valgaclinodactyly V, pectus deformityclinodactyly V, bilateral M. Perthesbrachymetacarpia,scoliosisOther featuresadducted thumbs, feet edema, short neck, wide fontanellenrpostnatal growth retardationobstruction of nasolacrimal ductnrbronchial hyperreactivity in early childhoodpostnatal growth retardation, hearing lossAbbreviations are as follows: nr, not reported; VSD, ventricular septal defect. Open table in a new tab Abbreviations are as follows: nr, not reported; VSD, ventricular septal defect. Individual 1 is a male infant with healthy, unrelated parents from Cameroon with an unremarkable family history. He was delivered in the 39th week of pregnancy with a birth weight of 2,770 g (−1.5 SD), length of 45.5 cm (−2 SD), and head circumference of 33 cm (−1.6 SD). The diagnosis of Catel-Manzke syndrome was made at the age of 6 days. Intubation and ventilation were required due to a Pierre Robin sequence with severe retrognathia and cleft palate (Figures 1A and 1B ). He had bilateral radial deviation and clinodactyly of the second digit and a mild ulnar deviation of the third and fourth finger. Radiographs showed the typical Manzke dysostosis (Figures 1C and 1D). Additionally, he had a wide anterior fontanelle, low set ears with prominent anthelices, a short neck, short humeri and femora, adducted thumbs, edema of the feet and eyelids, and short toes. Radiographs of humeri, femora, and pelvis were normal. When last examined at the age of 18 months, he still had retrognathia and a tracheostomy. However, he had developed well, was able to walk, and had started speaking. His height was 77 cm (−2.7 SD), his head circumference 48.5 cm (+0.2 SD), and his weight 10.2 kg (−0.3 SD). Individual 2 is the second child of British and South American nonconsanguineous parents and has a healthy older sister. She was delivered at term after an uncomplicated pregnancy, with birth weight of 3,534 g (+0.3 SD) and head circumference of 35 cm (+0.25 SD). She was noted to have a cleft palate, micrognathia, bilateral hand abnormalities, mild hypertelorism, upslanting palpebral fissures, and thin eyebrows (Figures 2A–2D and 2F ). Echocardiogram revealed a ventricular septal defect (VSD), and hand radiographs performed at the age of 3 months showed a triangular-shaped bone inserted between the second metacarpal and its proximal phalanx bilaterally causing radial deviation of the index fingers. On the left hand an additional pin-shaped ossification center was visible (Figures 2E and 2G). She underwent cleft palate repair and jaw distraction procedures. The VSD closed spontaneously, and her development progressed normally. When last seen at the age of 3.5 years, her height was 90 cm (−2.7 SD), head circumference was 49.3 cm (−0.4 SD), and weight was 13.36 kg (+0.2 SD). Individuals 3, 4, and 5 correspond to individuals 1, 2, and 3 reported by Manzke and coworkers in 2008 and are of German descent.5Manzke H. Lehmann K. Klopocki E. Caliebe A. Catel-Manzke syndrome: two new patients and a critical review of the literature.Eur. J. Med. Genet. 2008; 51: 452-465Crossref PubMed Scopus (29) Google Scholar Individual 5 is the individual first described by Catel and Manzke. No DNA samples of the parents of individual 3 were available. Individual 4 was last examined at the age of almost 20 years. She underwent bilateral osteotomy due to genua valga but is otherwise healthy. The mother of individual 4 was included in our study; the father, however, was unavailable for segregation analysis. Individual 5 has two unaffected children from a nonconsanguineous marriage who were included in our study. His unaffected parents were not available for analysis. Individual 6 is the second child of healthy, unrelated Dutch parents and is now a 17-year-old adolescent who was already reported by Kant and coworkers in 1998.18Kant S.G. Oudshoorn A. Gi C.V. Zonderland H.M. Van Haeringen A. The Catel-Manzke syndrome in a female infant.Genet. Couns. 1998; 9: 187-190PubMed Google Scholar Growth and development were normal. She now has thin eyebrows, mild proptosis, low-set ears with dysplastic helices, a long columella, and a small mouth with high palate and slightly bifid uvula. She developed Perthes disease affecting the right hip at the age of 9 years and the left hip at the age of about 13 years. Her right leg is longer because of incomplete recovery of the left hip. She has subluxation of both knees, hypermobile elbow joints, and broad feet. Her older brother is unaffected. Individual 7 is a woman who was reported as individual 3 by Nizon and coworkers in 2012 (Figures 1E and 1F).20Nizon M. Alanay Y. Tuysuz B. Kiper P.O. Geneviève D. Sillence D. Huber C. Munnich A. Cormier-Daire V. IMPAD1 mutations in two Catel-Manzke like patients.Am. J. Med. Genet. A. 2012; 158A: 2183-2187Crossref PubMed Scopus (26) Google Scholar She has healthy, unrelated Northern French parents, who were not available for segregation analysis. Individuals of family 1 (proband and parents), family 2 (proband and parents), family 4 (proband and mother), family 5 (proband and children), and the affected individual of family 7 were subjected to exome sequencing after approval of the ethical boards of the Charité, the Christian-Albrecht-University, and the University of Paris Decartes. The probands and/or parents gave their written consent for genetic testing and publication of images. High-throughput sequencing and data processing were performed in NGS-core facilities of the respective universities or collaborating service providers. Eight exomes from individuals 2, 4, 5, and their relatives were captured with SeqCap EZ Human Exome Library version 2.0 kit (Roche NimbleGen). The finished libraries were sequenced on an Illumina HiSeq 2000 sequencing instrument (Illumina) with a paired-end 2 × 100 bp protocol. On average, this resulted in 6.7 Gb of mapped unique sequences with a mean coverage of 80×, i.e., 20× coverage for 91% of target sequences and 80× coverage for 85% of target sequences. The CCG VARBANK pipeline v.2.1 was used for data analysis and filtering with bwa-aln plus hg19 for mapping of reads in combination with the GATK toolkit for base quality score recalibration (BQSR), local realignment, and variant quality score recalibration (VQSR). GATK and samtools mpileup were used to call SNVs and short indels. Software developed in-house was used to annotate variants on a functional level (see Web Resources). Four DNA samples, including individual 1, his parents, and individual 7, were subjected to exome analysis with SureSelect All Exon Kit V2 (Agilent) for targeted enrichment followed by sequencing with Illumina’s HiSeq system (paired-end 2 × 100 bp). Sequence reads were mapped to the haploid human reference genome (hg19) using Novoalign (Novocraft Technologies). Single-nucleotide variants (SNVs) and short insertions and deletions (indels) were called with GATK toolkit according to the best practice guidelines and resulted in a high-quality exome variant set.32Li H. A statistical framework for SNP calling, mutation discovery, association mapping and population genetical parameter estimation from sequencing data.Bioinformatics. 2011; 27: 2987-2993Crossref PubMed Scopus (3130) Google Scholar, 33Heinrich V. Kamphans T. Stange J. Parkhomchuk D. Hecht J. Dickhaus T. Robinson P.N. Krawitz P.M. Estimating exome genotyping accuracy by comparing to data from large scale sequencing projects.Genome Med. 2013; 5: 69Crossref PubMed Scopus (21) Google Scholar, 34DePristo M.A. Banks E. Poplin R. Garimella K.V. Maguire J.R. Hartl C. Philippakis A.A. del Angel G. Rivas M.A. Hanna M. et al.A framework for variation discovery and genotyping using next-generation DNA sequencing data.Nat. Genet. 2011; 43: 491-498Crossref PubMed Scopus (7101) Google Scholar The variant annotation on a functional level was performed with Jannovar and GeneTalk was used for filtering and further data analysis.35Jäger M. Wang K. Bauer S. Smedley D. Krawitz P. Robinson P.N. Jannovar: a java library for exome annotation.Hum. Mutat. 2014; 35: 548-555Crossref PubMed Scopus (47) Google Scholar, 36Kamphans T. Krawitz P.M. GeneTalk: an expert exchange platform for assessing rare sequence variants in personal genomes.Bioinformatics. 2012; 28: 2515-2516Crossref PubMed Scopus (45) Google Scholar Because a separate analysis of the families did not yield a single candidate gene, we combined all affected individuals into a case group and selected control subjects that matched the ethnicity and data quality of the cases for filtering. We assumed that the prevalence of the disorder is below 1 in 1,000,000 and has a high penetrance. We considered a recessive as well as a dominant mode of inheritance. Because none of the families had affected individuals in more than one generation, we filtered for potential de novo mutations when analyzing the dominant model of inheritance and could not identify a candidate gene. For the analysis of a recessive mode of inheritance, we first filtered the sequence variants in the samples based on genotype frequency data from large population genetics studies.37Abecasis G.R. Auton A. Brooks L.D. DePristo M.A. Durbin R.M. Handsaker R.E. Kang H.M. Marth G.T. McVean G.A. 1000 Genomes Project ConsortiumAn integrated map of genetic variation from 1,092 human genomes.Nature. 2012; 491: 56-65Crossref PubMed Scopus (5677) Google Scholar, 38Tennessen J.A. Bigham A.W. O’Connor T.D. Fu W. Kenny E.E. Gravel S. McGee S. Do R. Liu X. Jun G. et al.Broad GOSeattle GONHLBI Exome Sequencing ProjectEvolution and functional impact of rare coding variation from deep sequencing of human exomes.Science. 2012; 337: 64-69Crossref PubMed Scopus (1213) Google Scholar We removed sequence variants that occurred in a homozygous state in more than one individual of the healthy controls. Alleles that had a heterozygous state in the affected individuals were removed if their allele frequency was above 0.01 in healthy controls. The analysis of the autosomal-recessive model of inheritance yielded three candidate genes: MUC4 (MIM 158372), MUC6 (MIM 158374), and TGDS. Because mucin genes are known to be highly variable, we focused on TGDS as the most likely candidate gene. The following variants in TGDS (RefSeq accession number NM_014305.2) were identified: c.892A>G (p.Asn298Asp), c.270_271del (p.Lys91Asnfs∗22), c.298G>T (p.Ala100Ser), c.294T>G (p.Phe98Leu), and c.269A>G (p.Glu90Gly). We analyzed two additional individuals with Catel-Manzke syndrome by Sanger sequencing of all coding exons of TGDS and identified the homozygous variant c.298G>T in individual 3 and compound heterozygosity for the variants c.700T>C (p.Tyr234His); c.298G>T in individual 6. In total, six different variants (five missense and one nonsense) in TGDS were detected (Table 1). All candidate mutations were validated by ABI Sanger sequencing (sequencing primers are available upon request). Sanger sequencing demonstrated a biparental mode of inheritance of the compound heterozygous mutations in the parents except individual 7 whose parents were not available. We analyzed seven individuals with Catel-Manzke syndrome and all of them carried homozygous or compound heterozygous mutations in TGDS. The function prediction algorithm MutationTaster39Schwarz J.M. Rödelsperger C. Schuelke M. Seelow D. MutationTaster evaluates disease-causing potential of sequence alterations.Nat. Methods. 2010; 7: 575-576Crossref PubMed Scopus (2123) Google Scholar classified all variants as disease causing. SIFT40Kumar P. Henikoff S. Ng P.C. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm.Nat. Protoc. 2009; 4: 1073-1081Crossref PubMed Scopus (5006) Google Scholar predicted only the amino acid change p.Phe98Leu and p.Tyr234His to be “tolerated,” and PolyPhen-241Adzhubei I.A. Schmidt S. Peshkin L. Ramensky V.E. Gerasimova A. Bork P. Kondrashov A.S. Sunyaev S.R. A method and server for predicting damaging missense mutations.Nat. Methods. 2010; 7: 248-249Crossref PubMed Scopus (9290) Google Scholar predicted only the amino acid change p.Phe98Leu to be “benign.” All other alterations were also predicted to be “probably damaging” or “damaging.” The differences in prediction outputs are most likely due to different protein sequence alignments.42Karchin R. Next generation tools for the annotation of human SNPs.Brief. Bioinform. 2009; 10: 35-52Crossref PubMed Scopus (87) Google Scholar The positions Ala100 and Tyr234 are completely conserved throughout evolution including E. coli (Figure 3B). The position Glu90 is conserved in zebrafish, the position Phe98 in C. elegans, and the position Asn298 in frog (not shown). Altogether we classify all substitutions to be disease causing. The amino acid change p.Lys91Asnfs∗22 is predicted to cause nonsense-mediated decay due to the truncation of the protein with the loss of 229 aa residues (out of a total of 350) at the C terminus. Except for c.298G>T and c.270_271del, all identified variants were not previously reported in the databases. The missense mutation c.298G>T is a known variant, rs140430952, and was observed in a heterozygous state in 9 out of 4,300 healthy individuals of European descent that were analyzed in the National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP) and in 40 out of 61,377 individuals that were analyzed by the Exome Aggregation Consortium (ExAC). The variant c.270_271del was observed in a heterozygous state in 2 out of 2,132 individuals of African descent in the ESP data and in 4 out of 61,447 individuals in the ExAC data. However, both sequence variants, c.298T and c.270_271, did not occur in a homozygous state in healthy control subjects, supporting our hypothesis that these alleles are pathogenic. If we assume a carrier rate of 0.002 for c.298T in the general European population, we would expect a homozygous individual in 1 out of 1,000,000, which is in good agreement with the estimated prevalence for Catel-Manzke syndrome. The relatively high frequency of c.298T in the European population might be due to a founder effect. We extracted sequence variants around c.298 from the available exome data for all affected individuals and estimated the haplotypes with the statistical software package PHASE v.2.1.43Stephens M. Smith N.J. Donnelly P. A new statistical method for haplotype reconstruction from population data.Am. J. Hum. Genet. 2001; 68: 978-989Abstract Full Text Full Text PDF PubMed Scopus (6431) Google Scholar Based on ten informative markers, we could reconstruct a 50 kb haplotype that is shared by all individuals with the pathogenic allele c.298T, supporting our hypothesis of a founder mutation (Tables S1–S3 available online). TGDS (dTDP-D-glucose 4,6-dehydratase/growth-inhibiting protein 21) is an evolutionarily conserved 350 aa protein belonging to the short-chain dehydrogenase/reductase (SDR) family. It shares a sequence identity of 35% with its E. coli ortholog,44Altschul S.F. Gish W. Miller W. Myers E.W. Lipman D.J. Basic local alignment search tool.J. Mol. Biol. 1990; 215: 403-410Crossref PubMed Scopus (70353) Google Scholar which catalyzes the synthesis of dTDP-4-oxo-6-deoxy-D-glucose from dTDP-glucose as part of the rhamnose pathway. Because rhamnose, a common component of the cell wall and the capsule of many pathogenic bacteria, does not exist in humans,45Giraud M.F. Naismith J.H. The rhamnose pathway.Curr. Opin. Struct. Biol. 2000; 10: 687-696Crossref PubMed Scopus (178) Google Scholar the specific function of TGDS and dTDP-4-oxo-6-deoxy-D-glucose in humans is unknown. SDRs are structured as a one-domain Rossman fold that typically c" @default.
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• W2003994376 title "Homozygous and Compound-Heterozygous Mutations in TGDS Cause Catel-Manzke Syndrome" @default.
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