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Prenatal exome sequencing and chromosomal microarray analysis in fetal structural anomalies in a highly consanguineous population reveals a propensity of ciliopathy genes causing multisystem phenotypes

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Abstract

Fetal abnormalities are detected in 3% of all pregnancies and are responsible for approximately 20% of all perinatal deaths. Chromosomal microarray analysis (CMA) and exome sequencing (ES) are widely used in prenatal settings for molecular genetic diagnostics with variable diagnostic yields. In this study, we aimed to determine the diagnostic yield of trio-ES in detecting the cause of fetal abnormalities within a highly consanguineous population. In families with a history of congenital anomalies, a total of 119 fetuses with structural anomalies were recruited and DNA from invasive samples were used together with parental DNA samples for trio-ES and CMA. Data were analysed to determine possible underlying genetic disorders associated with observed fetal phenotypes. The cohort had a known consanguinity of 81%. Trio-ES led to diagnostic molecular genetic findings in 59 fetuses (with pathogenic/likely pathogenic variants) most with multisystem or renal abnormalities. CMA detected chromosomal abnormalities compatible with the fetal phenotype in another 7 cases. Monogenic ciliopathy disorders with an autosomal recessive inheritance were the predominant cause of multisystem fetal anomalies (24/59 cases, 40.7%) with loss of function variants representing the vast majority of molecular genetic abnormalities. Heterozygous de novo pathogenic variants were found in four fetuses. A total of 23 novel variants predicted to be associated with the phenotype were detected. Prenatal trio-ES and CMA detected likely causative molecular genetic defects in a total of 55% of families with fetal anomalies confirming the diagnostic utility of trio-ES and CMA as first-line genetic test in the prenatal diagnosis of multisystem fetal anomalies including ciliopathy syndromes.

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References

  • Abu-El-Haija A, Fineman J, Connolly AJ, Murali P, Judge LM, Slavotinek AM (2018) Two patients with FOXF1 mutations with alveolar capillary dysplasia with misalignment of pulmonary veins and other malformations: two different presentations and outcomes. Am J Med Genet A 176:2877–2881. https://doi.org/10.1002/ajmg.a.40641

    Article  CAS  PubMed  Google Scholar 

  • Abu-Safieh L, Abboud EB, Alkuraya H, Shamseldin H, Al-Enzi S, Al-Abdi L, Hashem M, Colak D, Jarallah A, Ahmad H, Bobis S, Nemer G, Bitar F, Alkuraya FS (2011) Mutation of IGFBP7 causes upregulation of BRAF/MEK/ERK pathway and familial retinal arterial macroaneurysms. Am J Hum Genet 89:313–319. https://doi.org/10.1016/j.ajhg.2011.07.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Al Husain M, AlBunyan M (1997) Consanguineous marriages in a Saudi population and the effect of inbreeding on prenatal and postnatal mortality. Ann Trop Paediatr 17:155–160. https://doi.org/10.1080/02724936.1997.11747879

    Article  CAS  PubMed  Google Scholar 

  • AlAbdi L, Alrashseed S, Alsulaiman A, Helaby R, Imtiaz F, Alhamed M, Alkuraya FS (2021) Residual risk for additional recessive diseases in consanguineous couples. Genet Med. https://doi.org/10.1038/s41436-021-01289-5

    Article  PubMed  Google Scholar 

  • Al-Hamed MH, Kurdi W, Alsahan N, Alabdullah Z, Abudraz R, Tulbah M, Alnemer M, Khan R, Al-Jurayb H, Alahmed A, Tahir AI, Khalil D, Edwards N, Al Abdulaziz B, Binhumaid FS, Majid S, Faquih T, El-Kalioby M, Abouelhoda M, Altassan N, Monies D, Meyer B, Sayer JA, Albaqumi M (2016) Genetic spectrum of Saudi Arabian patients with antenatal cystic kidney disease and ciliopathy phenotypes using a targeted renal gene panel. J Med Genet 53:338–347. https://doi.org/10.1136/jmedgenet-2015-103469

    Article  CAS  PubMed  Google Scholar 

  • Al-Hamed MH, Alsahan N, Tulbah M, Kurdi W, Ali W, Sayer JA, Imtiaz F (2020) Fetal anomalies associated with novel pathogenic variants in TMEM94. Genes (basel). https://doi.org/10.3390/genes11090967

    Article  Google Scholar 

  • Alkuraya FS (2013) Impact of new genomic tools on the practice of clinical genetics in consanguineous populations: the Saudi experience. Clin Genet 84:203–208. https://doi.org/10.1111/cge.12131

    Article  CAS  PubMed  Google Scholar 

  • Alsahan N, Alkuraya FS (2020) Confirming TBC1D32-related ciliopathy in humans. Am J Med Genet A. https://doi.org/10.1002/ajmg.a.61717

    Article  PubMed  Google Scholar 

  • American College of O, Gynecologists’ Committee on Practice B-O, Committee on G, Society for Maternal-Fetal M (2016) Practice bulletin no. 162: prenatal diagnostic testing for genetic disorders. Obstet Gynecol 127:e108–e122. https://doi.org/10.1097/AOG.0000000000001405

    Article  CAS  Google Scholar 

  • Bachmann-Gagescu R, Dempsey JC, Phelps IG, O’Roak BJ, Knutzen DM, Rue TC, Ishak GE, Isabella CR, Gorden N, Adkins J, Boyle EA, de Lacy N, O’Day D, Alswaid A, Ramadevi AR, Lingappa L, Lourenço C, Martorell L, Garcia-Cazorla À, Ozyürek H, Haliloğlu G, Tuysuz B, Topçu M, Chance P, Parisi MA, Glass IA, Shendure J, Doherty D (2015) Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity. J Med Genet 52:514–522. https://doi.org/10.1136/jmedgenet-2015-103087

    Article  CAS  PubMed  Google Scholar 

  • Beltrán-Valero de Bernabé D, Currier S, Steinbrecher A, Celli J, van Beusekom E, van der Zwaag B, Kayserili H, Merlini L, Chitayat D, Dobyns WB, Cormand B, Lehesjoki AE, Cruces J, Voit T, Walsh CA, van Bokhoven H, Brunner HG (2002) Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome. Am J Hum Genet 71:1033–1043. https://doi.org/10.1086/342975

    Article  PubMed  PubMed Central  Google Scholar 

  • Bergmann C, Fliegauf M, Brüchle NO, Frank V, Olbrich H, Kirschner J, Schermer B, Schmedding I, Kispert A, Kränzlin B, Nürnberg G, Becker C, Grimm T, Girschick G, Lynch SA, Kelehan P, Senderek J, Neuhaus TJ, Stallmach T, Zentgraf H, Nürnberg P, Gretz N, Lo C, Lienkamp S, Schäfer T, Walz G, Benzing T, Zerres K, Omran H (2008) Loss of nephrocystin-3 function can cause embryonic lethality, Meckel-Gruber-like syndrome, situs inversus, and renal-hepatic-pancreatic dysplasia. Am J Hum Genet 82:959–970. https://doi.org/10.1016/j.ajhg.2008.02.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bertoli-Avella AM, Beetz C, Ameziane N, Rocha ME, Guatibonza P, Pereira C, Calvo M, Herrera-Ordonez N, Segura-Castel M, Diego-Alvarez D, Zawada M, Kandaswamy KK, Werber M, Paknia O, Zielske S, Ugrinovski D, Warnack G, Kampe K, Iurașcu MI, Cozma C, Vogel F, Alhashem A, Hertecant J, Al-Shamsi AM, Alswaid AF, Eyaid W, Al Mutairi F, Alfares A, Albalwi MA, Alfadhel M, Al-Sannaa NA, Reardon W, Alanay Y, Rolfs A, Bauer P (2021) Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort. Eur J Hum Genet 29:141–153. https://doi.org/10.1038/s41431-020-00713-9

    Article  CAS  PubMed  Google Scholar 

  • Best S, Wou K, Vora N, Van der Veyver IB, Wapner R, Chitty LS (2018) Promises, pitfalls and practicalities of prenatal whole exome sequencing. Prenat Diagn 38:10–19. https://doi.org/10.1002/pd.5102

    Article  CAS  PubMed  Google Scholar 

  • Bond J, Scott S, Hampshire DJ, Springell K, Corry P, Abramowicz MJ, Mochida GH, Hennekam RC, Maher ER, Fryns JP, Alswaid A, Jafri H, Rashid Y, Mubaidin A, Walsh CA, Roberts E, Woods CG (2003) Protein-truncating mutations in ASPM cause variable reduction in brain size. Am J Hum Genet 73:1170–1177. https://doi.org/10.1086/379085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Braun DA, Hildebrandt F (2017) Ciliopathies. Cold Spring Harb Perspect Biol. https://doi.org/10.1101/cshperspect.a028191

    Article  PubMed  PubMed Central  Google Scholar 

  • Chaki M, Hoefele J, Allen SJ, Ramaswami G, Janssen S, Bergmann C, Heckenlively JR, Otto EA, Hildebrandt F (2011) Genotype-phenotype correlation in 440 patients with NPHP-related ciliopathies. Kidney Int 80:1239–1245. https://doi.org/10.1038/ki.2011.284

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen YH, Grigelioniene G, Newton PT, Gullander J, Elfving M, Hammarsjö A, Batkovskyte D, Alsaif HS, Kurdi WIY, Abdulwahab F, Shanmugasundaram V, Devey L, Bacrot S, Brodszki J, Huber C, Hamel B, Gisselsson D, Papadogiannakis N, Jedrycha K, Gürtl-Lackner B, Chagin AS, Nishimura G, Aschenbrenner D, Alkuraya FS, Laurence A, Cormier-Daire V, Uhlig HH (2020) Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome. J Exp Med. https://doi.org/10.1084/jem.20191306

    Article  PubMed  PubMed Central  Google Scholar 

  • Copyright © (1993–2021) University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved., Seattle (WA)

  • Dillon OJ, Lunke S, Stark Z, Yeung A, Thorne N, Melbourne Genomics Health A, Gaff C, White SM, Tan TY (2018) Exome sequencing has higher diagnostic yield compared to simulated disease-specific panels in children with suspected monogenic disorders. Eur J Hum Genet 26:644–651. https://doi.org/10.1038/s41431-018-0099-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Donnelly JC, Platt LD, Rebarber A, Zachary J, Grobman WA, Wapner RJ (2014) Association of copy number variants with specific ultrasonographically detected fetal anomalies. Obstet Gynecol 124:83–90. https://doi.org/10.1097/aog.0000000000000336

    Article  PubMed  PubMed Central  Google Scholar 

  • El-Mouzan MI, Al-Salloum AA, Al-Herbish AS, Qurachi MM, Al-Omar AA (2007) Regional variations in the prevalence of consanguinity in Saudi Arabia. Saudi Med J 28:1881–1884

    PubMed  Google Scholar 

  • Findley TO, Northrup H (2021) The current state of prenatal detection of genetic conditions in congenital heart defects. Transl Pediatr 10:2157–2170. https://doi.org/10.21037/tp-20-315

    Article  PubMed  PubMed Central  Google Scholar 

  • Frank V, Habbig S, Bartram MP, Eisenberger T, Veenstra-Knol HE, Decker C, Boorsma RA, Göbel H, Nürnberg G, Griessmann A, Franke M, Borgal L, Kohli P, Völker LA, Dötsch J, Nürnberg P, Benzing T, Bolz HJ, Johnson C, Gerkes EH, Schermer B, Bergmann C (2013) Mutations in NEK8 link multiple organ dysplasia with altered Hippo signalling and increased c-MYC expression. Hum Mol Genet 22:2177–2185. https://doi.org/10.1093/hmg/ddt070

    Article  CAS  PubMed  Google Scholar 

  • Geis T, Rödl T, Topaloğlu H, Balci-Hayta B, Hinreiner S, Müller-Felber W, Schoser B, Mehraein Y, Hübner A, Zirn B, Hoopmann M, Reutter H, Mowat D, Schuierer G, Schara U, Hehr U, Kölbel H (2019) Clinical long-time course, novel mutations and genotype-phenotype correlation in a cohort of 27 families with POMT1-related disorders. Orphanet J Rare Dis 14:179. https://doi.org/10.1186/s13023-019-1119-0

    Article  PubMed  PubMed Central  Google Scholar 

  • Geremek M, Dudarewicz L, Obersztyn E, Paczkowska M, Smyk M, Sobecka K, Nowakowska B (2020) Null variants in AGRN cause lethal fetal akinesia deformation sequence. Clin Genet 97:634–638. https://doi.org/10.1111/cge.13677

    Article  CAS  PubMed  Google Scholar 

  • Gnanasambandam R, Rivera A, Vandorpe DH, Shmukler BE, Brugnara C, Snyder LM, Andolfo I, Iolascon A, Silveira PA, Hamerschlak N, Gottlieb P, Alper SL (2018) Increased red cell KCNN4 activity in sporadic hereditary xerocytosis associated with enhanced single channel pressure sensitivity of PIEZO1 mutant V598M. Hemasphere 2:e55. https://doi.org/10.1097/hs9.0000000000000055

    Article  PubMed  PubMed Central  Google Scholar 

  • Guo Y, Kartawinata M, Li J, Pickett HA, Teo J, Kilo T, Barbaro PM, Keating B, Chen Y, Tian L, Al-Odaib A, Reddel RR, Christodoulou J, Xu X, Hakonarson H, Bryan TM (2014) Inherited bone marrow failure associated with germline mutation of ACD, the gene encoding telomere protein TPP1. Blood 124:2767–2774. https://doi.org/10.1182/blood-2014-08-596445

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hafsi W, Badri T, Rice AS (2021) Bloom syndrome StatPearls. StatPearls Publishing. Copyright © 2021, StatPearls Publishing LLC., Treasure Island

    Google Scholar 

  • Ibrahim DM, Hansen P, Rodelsperger C, Stiege AC, Doelken SC, Horn D, Jager M, Janetzki C, Krawitz P, Leschik G, Wagner F, Scheuer T, Schmidt-von Kegler M, Seemann P, Timmermann B, Robinson PN, Mundlos S, Hecht J (2013) Distinct global shifts in genomic binding profiles of limb malformation-associated HOXD13 mutations. Genome Res 23:2091–2102. https://doi.org/10.1101/gr.157610.113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jansen FA, Blumenfeld YJ, Fisher A, Cobben JM, Odibo AO, Borrell A, Haak MC (2015) Array comparative genomic hybridization and fetal congenital heart defects: a systematic review and meta-analysis. Ultrasound Obstet Gynecol 45:27–35. https://doi.org/10.1002/uog.14695

    Article  CAS  PubMed  Google Scholar 

  • Jelin AC, Vora N (2018) Whole exome sequencing: applications in prenatal genetics. Obstet Gynecol Clin N Am 45:69–81. https://doi.org/10.1016/j.ogc.2017.10.003

    Article  Google Scholar 

  • Jenkins D, Bitner-Glindzicz M, Malcolm S, Hu CC, Allison J, Winyard PJ, Gullett AM, Thomas DF, Belk RA, Feather SA, Sun TT, Woolf AS (2005) De novo Uroplakin IIIa heterozygous mutations cause human renal adysplasia leading to severe kidney failure. J Am Soc Nephrol 16:2141–2149. https://doi.org/10.1681/ASN.2004090776

    Article  CAS  PubMed  Google Scholar 

  • Kohlhase J, Wischermann A, Reichenbach H, Froster U, Engel W (1998) Mutations in the SALL1 putative transcription factor gene cause Townes-Brocks syndrome. Nat Genet 18:81–83. https://doi.org/10.1038/ng0198-81

    Article  CAS  PubMed  Google Scholar 

  • Kopanos C, Tsiolkas V, Kouris A, Chapple CE, Albarca Aguilera M, Meyer R, Massouras A (2019) VarSome: the human genomic variant search engine. Bioinformatics 35:1978–1980. https://doi.org/10.1093/bioinformatics/bty897

    Article  CAS  PubMed  Google Scholar 

  • Laccone F, Schoner K, Krabichler B, Kluge B, Schwerdtfeger R, Schulze B, Zschocke J, Rehder H (2011) Desbuquois dysplasia type I and fetal hydrops due to novel mutations in the CANT1 gene. Eur J Hum Genet 19:1133–1137. https://doi.org/10.1038/ejhg.2011.101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lawson C, Blakemore KJ, Ryan R, Hooper JE, Tsimis M, Jelin A (2020) Sacral protuberance with cleft lip and palate: prenatal presentation of 3MC syndrome. Am J Med Genet A 182:1812–1814. https://doi.org/10.1002/ajmg.a.61624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee CN, Lin SY, Lin CH, Shih JC, Lin TH, Su YN (2012) Clinical utility of array comparative genomic hybridisation for prenatal diagnosis: a cohort study of 3171 pregnancies. BJOG 119:614–625. https://doi.org/10.1111/j.1471-0528.2012.03279.x

    Article  PubMed  Google Scholar 

  • Li J, Oehlert J, Snyder M, Stevenson DK, Shaw GM (2017) Fetal de novo mutations and preterm birth. PLoS Genet 13:e1006689. https://doi.org/10.1371/journal.pgen.1006689

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu HY, Zhou L, Zheng MY, Huang J, Wan S, Zhu A, Zhang M, Dong A, Hou L, Li J, Xu H, Lu B, Lu W, Liu P, Lu Y (2019) Diagnostic and clinical utility of whole genome sequencing in a cohort of undiagnosed Chinese families with rare diseases. Sci Rep 9:19365. https://doi.org/10.1038/s41598-019-55832-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lord J, McMullan DJ, Eberhardt RY, Rinck G, Hamilton SJ, Quinlan-Jones E, Prigmore E, Keelagher R, Best SK, Carey GK, Mellis R, Robart S, Berry IR, Chandler KE, Cilliers D, Cresswell L, Edwards SL, Gardiner C, Henderson A, Holden ST, Homfray T, Lester T, Lewis RA, Newbury-Ecob R, Prescott K, Quarrell OW, Ramsden SC, Roberts E, Tapon D, Tooley MJ, Vasudevan PC, Weber AP, Wellesley DG, Westwood P, White H, Parker M, Williams D, Jenkins L, Scott RH, Kilby MD, Chitty LS, Hurles ME, Maher ER, Prenatal Assessment of G, Exomes C (2019) Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study. Lancet 393:747–757. https://doi.org/10.1016/S0140-6736(18)31940-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Manolakos E, Vetro A, Garas A, Thomaidis L, Kefalas K, Kitsos G, Ziegler M, Liehr T, Zuffardi O, Papoulidis I (2014) Proximal 10q duplication in a child with severe central hypotonia characterized by array-comparative genomic hybridization: a case report and review of the literature. Exp Ther Med 7:953–957. https://doi.org/10.3892/etm.2014.1520

    Article  PubMed  PubMed Central  Google Scholar 

  • Monies D, Abouelhoda M, AlSayed M, Alhassnan Z, Alotaibi M, Kayyali H, Al-Owain M, Shah A, Rahbeeni Z, Al-Muhaizea MA, Alzaidan HI, Cupler E, Bohlega S, Faqeih E, Faden M, Alyounes B, Jaroudi D, Goljan E, Elbardisy H, Akilan A, Albar R, Aldhalaan H, Gulab S, Chedrawi A, Al Saud BK, Kurdi W, Makhseed N, Alqasim T, El Khashab HY, Al-Mousa H, Alhashem A, Kanaan I, Algoufi T, Alsaleem K, Basha TA, Al-Murshedi F, Khan S, Al-Kindy A, Alnemer M, Al-Hajjar S, Alyamani S, Aldhekri H, Al-Mehaidib A, Arnaout R, Dabbagh O, Shagrani M, Broering D, Tulbah M, Alqassmi A, Almugbel M, AlQuaiz M, Alsaman A, Al-Thihli K, Sulaiman RA, Al-Dekhail W, Alsaegh A, Bashiri FA, Qari A, Alhomadi S, Alkuraya H, Alsebayel M, Hamad MH, Szonyi L, Abaalkhail F, Al-Mayouf SM, Almojalli H, Alqadi KS, Elsiesy H, Shuaib TM, Seidahmed MZ, Abosoudah I, Akleh H, AlGhonaium A, Alkharfy TM, Al Mutairi F, Eyaid W, Alshanbary A, Sheikh FR, Alsohaibani FI, Alsonbul A, Al Tala S, Balkhy S, Bassiouni R, Alenizi AS, Hussein MH, Hassan S, Khalil M, Tabarki B, Alshahwan S, Oshi A, Sabr Y, Alsaadoun S, Salih MA, Mohamed S, Sultana H, Tamim A, El-Haj M, Alshahrani S, Bubshait DK, Alfadhel M et al (2017) The landscape of genetic diseases in Saudi Arabia based on the first 1000 diagnostic panels and exomes. Hum Genet 136:921–939. https://doi.org/10.1007/s00439-017-1821-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mutlu MB, Cetinkaya A, Koc N, Ceylaner G, Erguner B, Aydın H, Karaman S, Demirci O, Goksu K, Karaman A (2016) A novel missense mutation, p. (R102W) in WNT7A causes Al-Awadi Raas-Rothschild syndrome in a fetus. Eur J Med Genet 59:604–606. https://doi.org/10.1016/j.ejmg.2016.09.009

    Article  PubMed  Google Scholar 

  • Oates C, Taylor P (2016) Helping expectant mothers understand inadequate ultrasound images. Ultrasound 24:142–146. https://doi.org/10.1177/1742271X16651901

    Article  PubMed  PubMed Central  Google Scholar 

  • Olinger E, Alawi IA, Al Riyami MS, Salmi IA, Molinari E, Faqeih EA, Al-Hamed MH, Barroso-Gil M, Powell L, Al-Hussaini AA, Rahim KA, Almontashiri NAM, Miles C, Shril S, Hildebrandt F, Consortium GER, Wilson IJ, Sayer JA (2021) A discarded synonymous variant in NPHP3 explains nephronophthisis and congenital hepatic fibrosis in several families. Hum Mutat. https://doi.org/10.1002/humu.24251

    Article  PubMed  Google Scholar 

  • Petrovski S, Aggarwal V, Giordano JL, Stosic M, Wou K, Bier L, Spiegel E, Brennan K, Stong N, Jobanputra V, Ren Z, Zhu X, Mebane C, Nahum O, Wang Q, Kamalakaran S, Malone C, Anyane-Yeboa K, Miller R, Levy B, Goldstein DB, Wapner RJ (2019) Whole-exome sequencing in the evaluation of fetal structural anomalies: a prospective cohort study. Lancet 393:758–767. https://doi.org/10.1016/S0140-6736(18)32042-7

    Article  CAS  PubMed  Google Scholar 

  • Reuter MS, Chaturvedi RR, Liston E, Manshaei R, Aul RB, Bowdin S, Cohn I, Curtis M, Dhir P, Hayeems RZ, Hosseini SM, Khan R, Ly LG, Marshall CR, Mertens L, Okello JBA, Pereira SL, Raajkumar A, Seed M, Thiruvahindrapuram B, Scherer SW, Kim RH, Jobling RK (2020) The Cardiac Genome Clinic: implementing genome sequencing in pediatric heart disease. Genet Med 22:1015–1024. https://doi.org/10.1038/s41436-020-0757-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Riggs ER, Andersen EF, Cherry AM, Kantarci S, Kearney H, Patel A, Raca G, Ritter DI, South ST, Thorland EC, Pineda-Alvarez D, Aradhya S, Martin CL (2020) Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med 22:245–257. https://doi.org/10.1038/s41436-019-0686-8

    Article  PubMed  Google Scholar 

  • Roberts AM, Ware JS, Herman DS, Schafer S, Baksi J, Bick AG, Buchan RJ, Walsh R, John S, Wilkinson S, Mazzarotto F, Felkin LE, Gong S, MacArthur JA, Cunningham F, Flannick J, Gabriel SB, Altshuler DM, Macdonald PS, Heinig M, Keogh AM, Hayward CS, Banner NR, Pennell DJ, O’Regan DP, San TR, de Marvao A, Dawes TJ, Gulati A, Birks EJ, Yacoub MH, Radke M, Gotthardt M, Wilson JG, O’Donnell CJ, Prasad SK, Barton PJ, Fatkin D, Hubner N, Seidman JG, Seidman CE, Cook SA (2015) Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease. Sci Transl Med 7:27ra06. https://doi.org/10.1126/scitranslmed.3010134

    Article  CAS  Google Scholar 

  • Rump P, Letteboer TG, Gille JJ, Torringa MJ, Baerts W, van Gestel JP, Verheij JB, van Essen AJ (2006) Severe complications in a child with achondroplasia and two FGFR3 mutations on the same allele. Am J Med Genet A 140:284–290. https://doi.org/10.1002/ajmg.a.31084

    Article  CAS  PubMed  Google Scholar 

  • Salzano E, Raible SE, Kaur M, Wilkens A, Sperti G, Tilton RK, Bettini LR, Rocca A, Cocchi G, Selicorni A, Conlin LK, McEldrew D, Gupta R, Thakur S, Izumi K, Krantz ID (2018) Prenatal profile of Pallister-Killian syndrome: Retrospective analysis of 114 pregnancies, literature review and approach to prenatal diagnosis. Am J Med Genet A 176:2575–2586. https://doi.org/10.1002/ajmg.a.40499

    Article  CAS  PubMed  Google Scholar 

  • Saugier-Veber P, Marguet F, Lecoquierre F, Adle-Biassette H, Guimiot F, Cipriani S, Patrier S, Brasseur-Daudruy M, Goldenberg A, Layet V, Capri Y, Gerard M, Frebourg T, Laquerriere A (2017) Hydrocephalus due to multiple ependymal malformations is caused by mutations in the MPDZ gene. Acta Neuropathol Commun 5:36. https://doi.org/10.1186/s40478-017-0438-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schwartz I, Silva LR, Leistner S, Todeschini LA, Burin MG, Pina-Neto JM, Islam RM, Shah GN, Sly WS, Giugliani R (2003) Mucopolysaccharidosis VII: clinical, biochemical and molecular investigation of a Brazilian family. Clin Genet 64:172–175. https://doi.org/10.1034/j.1399-0004.2003.00119.x

    Article  CAS  PubMed  Google Scholar 

  • Schwerd T, Twigg SRF, Aschenbrenner D, Manrique S, Miller KA, Taylor IB, Capitani M, McGowan SJ, Sweeney E, Weber A, Chen L, Bowness P, Riordan A, Cant A, Freeman AF, Milner JD, Holland SM, Frede N, Muller M, Schmidt-Arras D, Grimbacher B, Wall SA, Jones EY, Wilkie AOM, Uhlig HH (2017) A biallelic mutation in IL6ST encoding the GP130 co-receptor causes immunodeficiency and craniosynostosis. J Exp Med 214:2547–2562. https://doi.org/10.1084/jem.20161810

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shaheen R, Ansari S, Mardawi EA, Alshammari MJ, Alkuraya FS (2013) Mutations in TMEM231 cause Meckel-Gruber syndrome. J Med Genet 50:160–162. https://doi.org/10.1136/jmedgenet-2012-101431

    Article  CAS  PubMed  Google Scholar 

  • Shaheen R, Al-Salam Z, El-Hattab AW, Alkuraya FS (2016a) The syndrome dysmorphic facies, renal agenesis, ambiguous genitalia, microcephaly, polydactyly and lissencephaly (DREAM-PL): Report of two additional patients. Am J Med Genet A 170:3222–3226. https://doi.org/10.1002/ajmg.a.37877

    Article  CAS  PubMed  Google Scholar 

  • Shaheen R, Patel N, Shamseldin H, Alzahrani F, Al-Yamany R, Aoisheer A, Ewida N, Anazi S, Alnemer M, Elsheikh M, Alfaleh K, Alshammari M, Alhashem A, Alangari AA, Salih MA, Kircher M, Daza RM, Ibrahim N, Wakil SM, Alaqeel A, Altowaijri I, Shendure J, Al-Habib A, Faqieh E, Alkuraya FS (2016b) Accelerating matchmaking of novel dysmorphology syndromes through clinical and genomic characterization of a large cohort. Genet Med 18:686–695. https://doi.org/10.1038/gim.2015.147

    Article  PubMed  Google Scholar 

  • Shaheen R, Szymanska K, Basu B, Patel N, Ewida N, Faqeih E, Al Hashem A, Derar N, Alsharif H, Aldahmesh MA, Alazami AM, Hashem M, Ibrahim N, Abdulwahab FM, Sonbul R, Alkuraya H, Alnemer M, Al Tala S, Al-Husain M, Morsy H, Seidahmed MZ, Meriki N, Al-Owain M, AlShahwan S, Tabarki B, Salih MA, Faquih T, El-Kalioby M, Ueffing M, Boldt K, Logan CV, Parry DA, Al Tassan N, Monies D, Megarbane A, Abouelhoda M, Halees A, Johnson CA, Alkuraya FS (2016c) Characterizing the morbid genome of ciliopathies. Genome Biol 17:242. https://doi.org/10.1186/s13059-016-1099-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shaheen R, Sebai MA, Patel N, Ewida N, Kurdi W, Altweijri I, Sogaty S, Almardawi E, Seidahmed MZ, Alnemri A, Madirevula S, Ibrahim N, Abdulwahab F, Hashem M, Al-Sheddi T, Alomar R, Alobeid E, Sallout B, AlBaqawi B, AlAali W, Ajaji N, Lesmana H, Hopkin RJ, Dupuis L, Mendoza-Londono R, Al Rukban H, Yoon G, Faqeih E, Alkuraya FS (2017) The genetic landscape of familial congenital hydrocephalus. Ann Neurol 81:890–897. https://doi.org/10.1002/ana.24964

    Article  CAS  PubMed  Google Scholar 

  • Shaheen R, Mark P, Prevost CT, AlKindi A, Alhag A, Estwani F, Al-Sheddi T, Alobeid E, Alenazi MM, Ewida N, Ibrahim N, Hashem M, Abdulwahab F, Bryant EM, Spinelli E, Millichap J, Barnett SS, Kearney HM, Accogli A, Scala M, Capra V, Nigro V, Fu D, Alkuraya FS (2019) Biallelic variants in CTU2 cause DREAM-PL syndrome and impair thiolation of tRNA wobble U34. Hum Mutat 40:2108–2120. https://doi.org/10.1002/humu.23870

    Article  CAS  PubMed  Google Scholar 

  • Shamseldin HE, Tulbah M, Kurdi W, Nemer M, Alsahan N, Al Mardawi E, Khalifa O, Hashem A, Kurdi A, Babay Z, Bubshait DK, Ibrahim N, Abdulwahab F, Rahbeeni Z, Hashem M, Alkuraya FS (2015) Identification of embryonic lethal genes in humans by autozygosity mapping and exome sequencing in consanguineous families. Genome Biol 16:116. https://doi.org/10.1186/s13059-015-0681-6

    Article  PubMed  PubMed Central  Google Scholar 

  • Shamseldin HE, Shaheen R, Ewida N, Bubshait DK, Alkuraya H, Almardawi E, Howaidi A, Sabr Y, Abdalla EM, Alfaifi AY, Alghamdi JM, Alsagheir A, Alfares A, Morsy H, Hussein MH, Al-Muhaizea MA, Shagrani M, Al Sabban E, Salih MA, Meriki N, Khan R, Almugbel M, Qari A, Tulba M, Mahnashi M, Alhazmi K, Alsalamah AK, Nowilaty SR, Alhashem A, Hashem M, Abdulwahab F, Ibrahim N, Alshidi T, AlObeid E, Alenazi MM, Alzaidan H, Rahbeeni Z, Al-Owain M, Sogaty S, Seidahmed MZ, Alkuraya FS (2020) The morbid genome of ciliopathies: an update. Genet Med 22:1051–1060. https://doi.org/10.1038/s41436-020-0761-1

    Article  PubMed  Google Scholar 

  • Srivastava S, Molinari E, Raman S, Sayer JA (2017) Many genes-one disease? Genetics of nephronophthisis (NPHP) and NPHP-associated disorders. Front Pediatr 5:287. https://doi.org/10.3389/fped.2017.00287

    Article  PubMed  Google Scholar 

  • Stankiewicz P, Sen P, Bhatt SS, Storer M, Xia Z, Bejjani BA, Ou Z, Wiszniewska J, Driscoll DJ, Maisenbacher MK, Bolivar J, Bauer M, Zackai EH, McDonald-McGinn D, Nowaczyk MM, Murray M, Hustead V, Mascotti K, Schultz R, Hallam L, McRae D, Nicholson AG, Newbury R, Durham-O’Donnell J, Knight G, Kini U, Shaikh TH, Martin V, Tyreman M, Simonic I, Willatt L, Paterson J, Mehta S, Rajan D, Fitzgerald T, Gribble S, Prigmore E, Patel A, Shaffer LG, Carter NP, Cheung SW, Langston C, Shaw-Smith C (2009) Genomic and genic deletions of the FOX gene cluster on 16q24.1 and inactivating mutations of FOXF1 cause alveolar capillary dysplasia and other malformations. Am J Hum Genet 84:780–791. https://doi.org/10.1016/j.ajhg.2009.05.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stankiewicz P, Kulkarni S, Dharmadhikari AV, Sampath S, Bhatt SS, Shaikh TH, Xia Z, Pursley AN, Cooper ML, Shinawi M, Paciorkowski AR, Grange DK, Noetzel MJ, Saunders S, Simons P, Summar M, Lee B, Scaglia F, Fellmann F, Martinet D, Beckmann JS, Asamoah A, Platky K, Sparks S, Martin AS, Madan-Khetarpal S, Hoover J, Medne L, Bonnemann CG, Moeschler JB, Vallee SE, Parikh S, Irwin P, Dalzell VP, Smith WE, Banks VC, Flannery DB, Lovell CM, Bellus GA, Golden-Grant K, Gorski JL, Kussmann JL, McGregor TL, Hamid R, Pfotenhauer J, Ballif BC, Shaw CA, Kang SH, Bacino CA, Patel A, Rosenfeld JA, Cheung SW, Shaffer LG (2012) Recurrent deletions and reciprocal duplications of 10q11.21q11.23 including CHAT and SLC18A3 are likely mediated by complex low-copy repeats. Hum Mutat 33:165–179. https://doi.org/10.1002/humu.21614

    Article  CAS  PubMed  Google Scholar 

  • Sun L, Tong H, Wang H, Yue Z, Liu T, Lin H, Li J, Wang C (2016) High mutation rate of NPHP3 in 18 Chinese infantile nephronophthisis patients. Nephrology (carlton) 21:209–216. https://doi.org/10.1111/nep.12563

    Article  CAS  Google Scholar 

  • Tadmouri GO, Nair P, Obeid T, Al Ali MT, Al Khaja N, Hamamy HA (2009) Consanguinity and reproductive health among Arabs. Reprod Health 6:17. https://doi.org/10.1186/1742-4755-6-17

    Article  PubMed  PubMed Central  Google Scholar 

  • Talkowski ME, Ordulu Z, Pillalamarri V, Benson CB, Blumenthal I, Connolly S, Hanscom C, Hussain N, Pereira S, Picker J, Rosenfeld JA, Shaffer LG, Wilkins-Haug LE, Gusella JF, Morton CC (2012) Clinical diagnosis by whole-genome sequencing of a prenatal sample. N Engl J Med 367:2226–2232. https://doi.org/10.1056/NEJMoa1208594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tallila J, Jakkula E, Peltonen L, Salonen R, Kestilä M (2008) Identification of CC2D2A as a Meckel syndrome gene adds an important piece to the ciliopathy puzzle. Am J Hum Genet 82:1361–1367. https://doi.org/10.1016/j.ajhg.2008.05.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tamary H, Dgany O (1993) Alpha-thalassemia. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, Amemiya A (eds) GeneReviews(®). University of Washington, Seattle

    Google Scholar 

  • Tartaglia M, Cordeddu V, Chang H, Shaw A, Kalidas K, Crosby A, Patton MA, Sorcini M, van der Burgt I, Jeffery S, Gelb BD (2004) Paternal germline origin and sex-ratio distortion in transmission of PTPN11 mutations in Noonan syndrome. Am J Hum Genet 75:492–497. https://doi.org/10.1086/423493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Toriyama M, Lee C, Taylor SP, Duran I, Cohn DH, Bruel AL, Tabler JM, Drew K, Kelly MR, Kim S, Park TJ, Braun DA, Pierquin G, Biver A, Wagner K, Malfroot A, Panigrahi I, Franco B, Al-Lami HA, Yeung Y, Choi YJ, Duffourd Y, Faivre L, Rivière JB, Chen J, Liu KJ, Marcotte EM, Hildebrandt F, Thauvin-Robinet C, Krakow D, Jackson PK, Wallingford JB (2016) The ciliopathy-associated CPLANE proteins direct basal body recruitment of intraflagellar transport machinery. Nat Genet 48:648–656. https://doi.org/10.1038/ng.3558

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tory K, Rousset-Rouvière C, Gubler MC, Morinière V, Pawtowski A, Becker C, Guyot C, Gié S, Frishberg Y, Nivet H, Deschênes G, Cochat P, Gagnadoux MF, Saunier S, Antignac C, Salomon R (2009) Mutations of NPHP2 and NPHP3 in infantile nephronophthisis. Kidney Int 75:839–847. https://doi.org/10.1038/ki.2008.662

    Article  CAS  PubMed  Google Scholar 

  • Toydemir RM, Rutherford A, Whitby FG, Jorde LB, Carey JC, Bamshad MJ (2006) Mutations in embryonic myosin heavy chain (MYH3) cause Freeman-Sheldon syndrome and Sheldon-Hall syndrome. Nat Genet 38:561–565. https://doi.org/10.1038/ng1775

    Article  CAS  PubMed  Google Scholar 

  • Turro E, Astle WJ, Megy K, Gräf S, Greene D, Shamardina O, Allen HL, Sanchis-Juan A, Frontini M, Thys C, Stephens J, Mapeta R, Burren OS, Downes K, Haimel M, Tuna S, Deevi SVV, Aitman TJ, Bennett DL, Calleja P, Carss K, Caulfield MJ, Chinnery PF, Dixon PH, Gale DP, James R, Koziell A, Laffan MA, Levine AP, Maher ER, Markus HS, Morales J, Morrell NW, Mumford AD, Ormondroyd E, Rankin S, Rendon A, Richardson S, Roberts I, Roy NBA, Saleem MA, Smith KGC, Stark H, Tan RYY, Themistocleous AC, Thrasher AJ, Watkins H, Webster AR, Wilkins MR, Williamson C, Whitworth J, Humphray S, Bentley DR, Kingston N, Walker N, Bradley JR, Ashford S, Penkett CJ, Freson K, Stirrups KE, Raymond FL, Ouwehand WH (2020) Whole-genome sequencing of patients with rare diseases in a national health system. Nature 583:96–102. https://doi.org/10.1038/s41586-020-2434-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vahidnezhad H, Youssefian L, Saeidian AH, Mahmoudi H, Touati A, Abiri M, Kajbafzadeh AM, Aristodemou S, Liu L, McGrath JA, Ertel A, Londin E, Kariminejad A, Zeinali S, Fortina P, Uitto J (2018) Recessive mutation in tetraspanin CD151 causes Kindler syndrome-like epidermolysis bullosa with multi-systemic manifestations including nephropathy. Matrix Biol 66:22–33. https://doi.org/10.1016/j.matbio.2017.11.003

    Article  CAS  PubMed  Google Scholar 

  • Vivante A, Hwang DY, Kohl S, Chen J, Shril S, Schulz J, van der Ven A, Daouk G, Soliman NA, Kumar AS, Senguttuvan P, Kehinde EO, Tasic V, Hildebrandt F (2017) Exome sequencing discerns syndromes in patients from consanguineous families with congenital anomalies of the kidneys and urinary tract. J Am Soc Nephrol 28:69–75. https://doi.org/10.1681/asn.2015080962

    Article  CAS  PubMed  Google Scholar 

  • Vora NL, Hui L (2018) Next-generation sequencing and prenatal ’omics: advanced diagnostics and new insights into human development. Genet Med 20:791–799. https://doi.org/10.1038/s41436-018-0087-4

    Article  PubMed  PubMed Central  Google Scholar 

  • Vora NL, Powell B, Brandt A, Strande N, Hardisty E, Gilmore K, Foreman AKM, Wilhelmsen K, Bizon C, Reilly J, Owen P, Powell CM, Skinner D, Rini C, Lyerly AD, Boggess KA, Weck K, Berg JS, Evans JP (2017) Prenatal exome sequencing in anomalous fetuses: new opportunities and challenges. Genet Med 19:1207–1216. https://doi.org/10.1038/gim.2017.33

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang J, Chen L, Zhou C, Wang L, Xie H, Xiao Y, Zhu H, Hu T, Zhang Z, Zhu Q, Liu Z, Liu S, Wang H, Xu M, Ren Z, Yu F, Cram DS, Liu H (2018) Prospective chromosome analysis of 3429 amniocentesis samples in China using copy number variation sequencing. Am J Obstet Gynecol 219(287):e1-28718. https://doi.org/10.1016/j.ajog.2018.05.030

    Article  Google Scholar 

  • Wapner RJ, Martin CL, Levy B, Ballif BC, Eng CM, Zachary JM, Savage M, Platt LD, Saltzman D, Grobman WA, Klugman S, Scholl T, Simpson JL, McCall K, Aggarwal VS, Bunke B, Nahum O, Patel A, Lamb AN, Thom EA, Beaudet AL, Ledbetter DH, Shaffer LG, Jackson L (2012) Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med 367:2175–2184. https://doi.org/10.1056/NEJMoa1203382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wojcik MH, Schwartz TS, Thiele KE, Paterson H, Stadelmaier R, Mullen TE, VanNoy GE, Genetti CA, Madden JA, Gubbels CS, Yu TW, Tan WH, Agrawal PB (2019) Infant mortality: the contribution of genetic disorders. J Perinatol 39:1611–1619. https://doi.org/10.1038/s41372-019-0451-5

    Article  PubMed  PubMed Central  Google Scholar 

  • Yates CL, Monaghan KG, Copenheaver D, Retterer K, Scuffins J, Kucera CR, Friedman B, Richard G, Juusola J (2017) Whole-exome sequencing on deceased fetuses with ultrasound anomalies: expanding our knowledge of genetic disease during fetal development. Genet Med 19:1171–1178. https://doi.org/10.1038/gim.2017.31

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank all families who participated in the study. We acknowledge the support of the Saudi Human Genome Program as well as the Saudi Diagnostic Laboratory administration and staff. We thank the Saudi Human Genome Program, King Abdulaziz City for Science and Technology (KACST), Saudi Arabia. The authors declare no conflict of interest.

Funding

JAS is funded by Kidney Research UK and the Northern Counties Kidney Research Fund.

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Authors and Affiliations

  1. Centre for Genomic Medicine, King Faisal Specialist Hospital and Research Centre, MBC# 26, P. O. Box 3354, Riyadh, Saudi Arabia

    Mohamed H. Al-Hamed, Dorota Monies, Zeeshan Shah, Rana Akili, Laila Alquayt, Samia Hagos, Mohamed Abouelhoda, Khushnooda Ramzan & Faiqa Imtiaz

  2. Saudi Diagnostics Laboratory, KFSHI, P.O.BOX 6802, Riyadh, 12311, Saudi Arabia

    Mohamed H. Al-Hamed, Rafiullah Rafiullah, Mirna Assoum, Afaf AlOtaibi, Wafaa Ali, Amal AlShammasi, Hadeel Elbardisy, Asma Akilan, Nora Almuhana, Abrar AlKhalifah & Faiqa Imtiaz

  3. Department of Obstetrics and Genecology, King Faisal Specialist Hospital and Research Centre, P. O. Box 3354, Riyadh, 11211, Saudi Arabia

    Wesam Kurdi, Rubina Khan, Maha Tulbah, Maha AlNemer, Nada AlSahan, Maisoon AlMugbel, Gawaher Almutairi, Wardah AlMubarak, Samia AlDawoud, Saja AlAmri, Bashayer Saeed, Hanifa Bukhari & Mohannad Ali

  4. Medical Genetics Department, King Faisal Specialist Hospital and Research Centre, P. O. Box 3354, Riyadh, Saudi Arabia

    Zuhair Rahbeeni & Nada Derar

  5. King Abdulaziz Medical City/King Saud bin Abdulaziz University for Health Science, Jeddah, Saudi Arabia

    Fahad Hakami

  6. Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK

    John A. Sayer

  7. Renal Services, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE7 7DN, UK

    John A. Sayer

  8. NIHR Newcastle Biomedical Research Centre, Newcastle University, Tyne and Wear, Newcastle upon Tyne, NE4 5PL, UK

    John A. Sayer

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  1. Mohamed H. Al-Hamed
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Contributions

MHA-H. JAS and FI conceived the study and participated in its design, coordination, drafted and revised the manuscript. WK, RK, MT, MAN, NS and MM participated in the clinical diagnosis of the cases. MHA-H, RR, MA, ZR, ND, KR, JAS and FH participated in exome analysis. AO, WA, AS, RA, LQ, HB, AA, NM and AK carried out all technical aspects of molecular diagnosis. GM, WM, SD, SA, BS, HB, and MA participated in the collection of data of enrolled cases. JAS revised the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Mohamed H. Al-Hamed or Faiqa Imtiaz.

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Conflict of interest

The authors have no conflicts of interest to declare.

Ethical approval

The study was approved by the Research Advisory Council at King Faisal Specialist Hospital and Research Centre (KFSH&RC), Riyadh, Saudi Arabia (RAC# 2211035).

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Informed consent was obtained from all individual participants included in the study.

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Not applicable.

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Al-Hamed, M.H., Kurdi, W., Khan, R. et al. Prenatal exome sequencing and chromosomal microarray analysis in fetal structural anomalies in a highly consanguineous population reveals a propensity of ciliopathy genes causing multisystem phenotypes. Hum Genet 141, 101–126 (2022). https://doi.org/10.1007/s00439-021-02406-9

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