title: Accelerating matchmaking of novel dysmorphology syndromes through clinical and genomic characterization of a large cohort.
abstract: Dysmorphology syndromes are among the most common referrals to clinical genetics specialists. Inability to match the dysmorphology pattern to a known syndrome can pose a major diagnostic challenge. With an aim to accelerate the establishment of new syndromes and their genetic etiology, we describe our experience with multiplex consanguineous families that appeared to represent novel autosomal recessive dysmorphology syndromes at the time of evaluation.
  
  
  
  Combined autozygome/exome analysis of multiplex consanguineous families with apparently novel dysmorphology syndromes.
  
  
  
  Consistent with the apparent novelty of the phenotypes, our analysis revealed a strong candidate variant in genes that were novel at the time of the analysis in the majority of cases, and 10 of these genes are published here for the first time as novel candidates (CDK9, NEK9, ZNF668, TTC28, MBL2, CADPS, CACNA1H, HYAL2, CTU2, and C3ORF17). A significant minority of the phenotypes (6/31, 19%), however, were caused by genes known to cause Mendelian phenotypes, thus expanding the phenotypic spectrum of the diseases linked to these genes. The conspicuous inheritance pattern and the highly specific phenotypes appear to have contributed to the high yield (90%) of plausible molecular diagnoses in our study cohort.
  
  
  
  Reporting detailed clinical and genomic analysis of a large series of apparently novel dysmorphology syndromes will likely lead to a trend to accelerate the establishment of novel syndromes and their underlying genes through open exchange of data for the benefit of patients, their families, health-care providers, and the research community.Genet Med 18 7, 686-695.
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Ranad
authors.initials: R
authors.lastname: Shaheen
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Nisha
authors.initials: N
authors.lastname: Patel
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Hanan
authors.initials: H
authors.lastname: Shamseldin
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Fatema
authors.initials: F
authors.lastname: Alzahrani
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Ruah
authors.initials: R
authors.lastname: Al-Yamany
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Agaadir
authors.initials: A
authors.lastname: ALMoisheer
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Nour
authors.initials: N
authors.lastname: Ewida
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Shamsa
authors.initials: S
authors.lastname: Anazi
authors.affiliation: Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Maha
authors.initials: M
authors.lastname: Alnemer
authors.affiliation: Department of Obstetrics and Gynecology, Suliman AlHabib Hospital, Riyadh, Saudi Arabia.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Elsheikh
authors.affiliation: Department of Obstetrics and Gynecology, Suliman AlHabib Hospital, Riyadh, Saudi Arabia.|Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Khaled
authors.initials: K
authors.lastname: Alfaleh
authors.affiliation: Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Muneera
authors.initials: M
authors.lastname: Alshammari
authors.affiliation: Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
authors.forename: Amal
authors.initials: A
authors.lastname: Alhashem
authors.affiliation: Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Abdullah A
authors.initials: AA
authors.lastname: Alangari
authors.affiliation: Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Mustafa A
authors.initials: MA
authors.lastname: Salih
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Kircher
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
authors.forename: Riza M
authors.initials: RM
authors.lastname: Daza
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Niema
authors.initials: N
authors.lastname: Ibrahim
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Salma M
authors.initials: SM
authors.lastname: Wakil
authors.affiliation: Department of Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Alaqeel
authors.affiliation: Department of Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Ikhlas
authors.initials: I
authors.lastname: Altowaijri
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.affiliation: Department of Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Amro
authors.initials: A
authors.lastname: Al-Habib
authors.affiliation: Department of Pediatrics, King Fahad Medical City, Riyadh, Saudi Arabia.
authors.forename: Eissa
authors.initials: E
authors.lastname: Faqieh
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.|Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
authors.forename: Fowzan S
authors.identifier: 0000-0003-4158-341X
authors.initials: FS
authors.lastname: Alkuraya
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis* / Q000235:genetics / Q000503:physiopathology; D003241:Consanguinity; D012734:Disorders of Sex Development / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology; D059472:Exome / Q000235:genetics*; D005260:Female; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007003:Hypoglycemia / Q000175:diagnosis* / Q000235:genetics / Q000503:physiopathology; D008297:Male; D008831:Microcephaly / Q000175:diagnosis* / Q000235:genetics / Q000503:physiopathology; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D017422:Sequence Analysis, DNA / Q000379:methods