Genome Analysis for Disease Variant Identification

Unravelling human developmental disease

Developmental disorders are characterized by congenital malformations, abnormalities in growth and/or in neurological development. Although developmental disorders are individually rare, collectively they affect 2% of the population, representing a major health and economic burden for society. Because an important proportion of developmental disorders are caused by genetic mutations, affected individuals often undergo extensive testing involving microarrays or Next Generation Sequencing. For affected families, a clear genetic diagnosis is key to understanding the cause of their disease, receiving better medical treatment and making informed health-related decisions. However, despite embarking on diagnostic odysseys involving microarrays, whole exome sequencing or even whole genome sequencing, over 50% of individuals with developmental disorders remain without genetic diagnosis. This diagnostic gap exposes the limitations of current technologies to detect and interpret disease-causing mutations. For instance, whole genome sequencing can detect mutations throughout the genome but pinpointing a disease-causing mutation among hundreds of thousands of benign variants remains a daunting task. Thus, accurate identification of disease-causing mutations, especially in non-coding regions of the genome, currently represents a major challenge in human genetics.

To address this challenge, we are applying state-of-the-art functional genomics technologies to identify pathogenic mutations underlying human developmental disease and dissect the molecular mechanism through which these alterations disrupt human development. Our research aims to better understand the genetic causes and mechanisms of currently unsolved developmental disorders. Ultimately, our goal is to translate results from basic research carried out at the lab bench into the clinic by improving current methods of genetic diagnosis and setting a base on which to provide better medical treatment and accurate genetic counselling to individuals affected by developmental disorders.

Selected publications

Spielmann M, Lupiáñez DG, Mundlos S.
Structural variation in the 3D genome.
Nat Rev Genet. 2018 Jul;19(7):453-467. Review.
Flöttmann R, Kragesteen BK, Geuer S, Socha M, Allou L, Sowińska-Seidler A, Bosquillon de Jarcy L, Wagner J, Jamsheer A, Oehl-Jaschkowitz B, Wittler L, de Silva D, Kurth I, Maya I, Santos-Simarro F, Hülsemann W, Klopocki E, Mountford R, Fryer A, Borck G, Horn D, Lapunzina P, Wilson M, Mascrez B, Duboule D, Mundlos S, Spielmann M.
Noncoding copy-number variations are associated with congenital limb malformation.
Genet Med. 2018 Jun;20(6):599-607. Epub 2017 Oct 12
Knaus A, Pantel JT, Pendziwiat M, Hajjir N, Zhao M, Hsieh TC, Schubach M, Gurovich Y, Fleischer N, Jäger M, Köhler S, Muhle H, Korff C, Møller RS, Bayat A, Calvas P, Chassaing N, Warren H, Skinner S, Louie R, Evers C, Bohn M, Christen HJ, van den Born M, Obersztyn E, Charzewska A, Endziniene M, Kortüm F, Brown N, Robinson PN, Schelhaas HJ, Weber Y, Helbig I, Mundlos S, Horn D, Krawitz PM.
Characterization of glycosylphosphatidylinositol biosynthesis defects by clinical features, flow cytometry, and automated image analysis.
Genome Med. 2018 Jan 9;10(1):3
Spielmann M, Hernandez-Miranda LR, Ceccherini I, Weese-Mayer DE, Kragesteen BK, Harabula I, Krawitz P, Birchmeier C, Leonard N, Mundlos S.
Mutations in MYO1H cause a recessive form of central hypoventilation with autonomic dysfunction.
J Med Genet. 2017 Nov;54(11):754-761. Epub 2017 Aug 4.
Afzal M, Zaman Q, Kornak U, Mundlos S, Malik S, Flöttmann R.
Novel splice mutation in LRP4 causes severe type of Cenani-Lenz syndactyly syndrome with oro-facial and skeletal symptoms.
Eur J Med Genet. 2017 Aug;60(8):421-425. Epub 2017 May 27.
Spielmann M, Kakar N, Tayebi N, Leettola C, Nürnberg G, Sowada N, Lupiáñez DG, Harabula I, Flöttmann R, Horn D, Chan WL, Wittler L, Yilmaz R, Altmüller J, Thiele H, van Bokhoven H, Schwartz CE, Nürnberg P, Bowie JU, Ahmad J, Kubisch C, Mundlos S, Borck G.
Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.
Genome Res. 2016 Feb;26(2):183-91.
Flöttmann R, Wagner J, Kobus K, Curry CJ, Savarirayan R, Nishimura G, Yasui N, Spranger J, Van Esch H, Lyons MJ, DuPont BR, Dwivedi A, Klopocki E, Horn D, Mundlos S, Spielmann M.
Microdeletions on 6p22.3 are associated with mesomelic dysplasia Savarirayan type.
J Med Genet. 2015 Jul;52(7):476-83. Epub 2015 Jun 1.
Lelieveld SH, Spielmann M, Mundlos S, Veltman JA, Gilissen C.
Comparison of Exome and Genome Sequencing Technologies for the Complete Capture of Protein Coding Regions.
Hum Mutat. 2015 Aug;36(8):815-22. Epub 2015 Jun 11.
Ehmke N, Caliebe A, Koenig R, Kant SG, Stark Z, Cormier-Daire V, Wieczorek D, Gillessen-Kaesbach G, Hoff K, Kawalia A, Thiele H, Altmüller J, Fischer-Zirnsak B, Knaus A, Zhu N, Heinrich V, Huber C, Harabula I, Spielmann M, Horn D, Kornak U, Hecht J, Krawitz PM, Nürnberg P, Siebert R, Manzke H, Mundlos S.
Homozygous and compound-heterozygous mutations in TGDS cause Catel-Manzke syndrome.
Am J Hum Genet. 2014 Dec 4;95(6):763-70.
Lohan S, Spielmann M, Doelken SC, Flöttmann R, Muhammad F, Baig SM, Wajid M, Hülsemann W, Habenicht R, Kjaer KW, Patil SJ, Girisha KM, Abarca-Barriga HH, Mundlos S, Klopocki E.
Microduplications encompassing the Sonic hedgehog limb enhancer ZRS are associated with Haas-type polysyndactyly and Laurin-Sandrow syndrome.
Clin Genet. 2014 Oct;86(4):318-25. Epub 2014 Feb 17.
Zemojtel T, Köhler S, Mackenroth L, Jäger M, Hecht J, Krawitz P, Graul-Neumann L, Doelken S, Ehmke N, Spielmann M, Oien NC, Schweiger MR, Krüger U, Frommer G, Fischer B, Kornak U, Flöttmann R, Ardeshirdavani A, Moreau Y, Lewis SE, Haendel M, Smedley D, Horn D, Mundlos S, Robinson PN.
Effective diagnosis of genetic disease by computational phenotype analysis of the disease-associated genome.
Sci Transl Med. 2014 Sep 3;6(252):252ra123.
Tayebi N, Jamsheer A, Flöttmann R, Sowinska-Seidler A, Doelken SC, Oehl-Jaschkowitz B, Hülsemann W, Habenicht R, Klopocki E, Mundlos S, Spielmann M.
Deletions of exons with regulatory activity at the DYNC1I1 locus are associated with split-hand/split-foot malformation: array CGH screening of 134 unrelated families.
Orphanet J Rare Dis. 2014 Jul 29;9:108.
Girisha KM, Bidchol AM, Kamath PS, Shah KH, Mortier GR, Mundlos S, Shah H.
A novel mutation (g.106737G>T) in zone of polarizing activity regulatory sequence (ZRS) causes variable limb phenotypes in Werner mesomelia.
Am J Med Genet A. 2014 Apr;164A(4):898-906. Epub 2014 Jan 29.

Go to Editor View