Genome Analysis for Disease Variant Identification
Rare diseases (defined as less than 1 in 2000) are in the majority of cases genetic in origin. Although rare diseases are individually rare, collectively they affect approx. 2% of the population, representing a major health and economic burden for society. In spite of extensive testing involving microarrays or Next Generation Sequencing over 50% of patients with developmental disorders remain without a 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.
So far, the non-coding genome has not been the focus of human genetics and Mendelian disease research on non-coding variants is only slowly emerging. This is mainly due to a large number of variants per genome and difficulties in interpreting non-coding variants. Together, this poses major problems that partially require the use of other/new technologies as well as new concepts of thinking and data interpretation. Our lab focuses on elucidating the patho-mechanisms underlying disease-causing mutations in the non-coding genome. Since there is currently no general concept to interpret mutations in the non-coding genome for their ability to cause disease, it is the aim of our group to develop such a framework and predict the regulatory effect of sturcutral variations (SVs) in a disease setting.
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.
Non-coding deletions identify Maenli lncRNA as a limb-specific En1 regulator
A CRISPR-Cas9–engineered mouse model for GPI-anchor deficiency mirrors human phenotypes and exhibits hippocampal synaptic dysfunctions
Structural Variants Create New Topological-Associated Domains and Ectopic Retinal Enhancer-Gene Contact in Dominant Retinitis Pigmentosa
Am J Hum Genet. 2020 Nov 5;107(5):802-814.
Hi-C Identifies Complex Genomic Rearrangements and TAD-Shuffling in Developmental Diseases
The American Journal of Human Genetics (2020), Volume 106, Issue 6, 872 - 884
Structural variation in the 3D genome.
Nat Rev Genet. 2018 Jul;19(7):453-467. Review.
Noncoding copy-number variations are associated with congenital limb malformation.
Genet Med. 2018 Jun;20(6):599-607. Epub 2017 Oct 12
Characterization of glycosylphosphatidylinositol biosynthesis defects by clinical features, flow cytometry, and automated image analysis.
Genome Med. 2018 Jan 9;10(1):3
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.
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.
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.
Microdeletions on 6p22.3 are associated with mesomelic dysplasia Savarirayan type.
J Med Genet. 2015 Jul;52(7):476-83. Epub 2015 Jun 1.
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.
Homozygous and compound-heterozygous mutations in TGDS cause Catel-Manzke syndrome.
Am J Hum Genet. 2014 Dec 4;95(6):763-70.
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.
Effective diagnosis of genetic disease by computational phenotype analysis of the disease-associated genome.
Sci Transl Med. 2014 Sep 3;6(252):252ra123.
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.
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.