The Utility of DNA Methylation Signatures in Directing Genome Sequencing Workflow: Kabuki Syndrome and CDK13-related Disorder

Overview

Journal Am J Med Genet A

Specialty Genetics

Date 2022 Jan 19

PMID 35043535

Authors

Ashish Marwaha

Gregory Costain

Cheryl Cytrynbaum

Roberto Mendoza-Londono

Lauren Chad

Zain Awamleh

Eric Chater-Diehl

Sanaa Choufani

Rosanna Weksberg

Affiliations

Soon will be listed here.

Abstract

Kabuki syndrome (KS) is a neurodevelopmental disorder characterized by hypotonia, intellectual disability, skeletal anomalies, and postnatal growth restriction. The characteristic facial appearance is not pathognomonic for KS as several other conditions demonstrate overlapping features. For 20-30% of children with a clinical diagnosis of KS, no causal variant is identified by conventional genetic testing of the two associated genes, KMT2D and KDM6A. Here, we describe two cases of suspected KS that met clinical diagnostic criteria and had a high gestalt match on the artificial intelligence platform Face2Gene. Although initial KS testing was negative, genome-wide DNA methylation (DNAm) was instrumental in guiding genome sequencing workflow to establish definitive molecular diagnoses. In one case, a positive DNAm signature for KMT2D led to the identification of a cryptic variant in KDM6A by genome sequencing; for the other case, a DNAm signature different from KS led to the detection of another diagnosis in the KS differential, CDK13-related disorder. This approach illustrates the clinical utility of DNAm signatures in the diagnostic workflow for the genome analyst or clinical geneticist-especially for disorders with overlapping clinical phenotypes.

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The utility of DNA methylation signatures in directing genome sequencing workflow: Kabuki syndrome and CDK13-related disorder.

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References

Aref-Eshghi E, Schenkel L, Lin H, Skinner C, Ainsworth P, Pare G . The defining DNA methylation signature of Kabuki syndrome enables functional assessment of genetic variants of unknown clinical significance. Epigenetics. 2017; 12(11):923-933. PMC: 5788422. DOI: 10.1080/15592294.2017.1381807. View

Hamilton M, Suri M . CDK13-related disorder. Adv Genet. 2019; 103:163-182. DOI: 10.1016/bs.adgen.2018.11.001. View

Gurovich Y, Hanani Y, Bar O, Nadav G, Fleischer N, Gelbman D . Identifying facial phenotypes of genetic disorders using deep learning. Nat Med. 2019; 25(1):60-64. DOI: 10.1038/s41591-018-0279-0. View

Dharmadhikari A, Ghosh R, Yuan B, Liu P, Dai H, Al Masri S . Copy number variant and runs of homozygosity detection by microarrays enabled more precise molecular diagnoses in 11,020 clinical exome cases. Genome Med. 2019; 11(1):30. PMC: 6525387. DOI: 10.1186/s13073-019-0639-5. View

Cytrynbaum C, Choufani S, Weksberg R . Epigenetic signatures in overgrowth syndromes: Translational opportunities. Am J Med Genet C Semin Med Genet. 2019; 181(4):491-501. DOI: 10.1002/ajmg.c.31745. View

Turinsky A, Choufani S, Lu K, Liu D, Mashouri P, Min D . EpigenCentral: Portal for DNA methylation data analysis and classification in rare diseases. Hum Mutat. 2020; 41(10):1722-1733. DOI: 10.1002/humu.24076. View

Zhang L, Pilarowski G, Merlo Pich E, Nakatani A, Dunlop J, Baba R . Inhibition of KDM1A activity restores adult neurogenesis and improves hippocampal memory in a mouse model of Kabuki syndrome. Mol Ther Methods Clin Dev. 2021; 20:779-791. PMC: 7940709. DOI: 10.1016/j.omtm.2021.02.011. View

Lederer D, Grisart B, Digilio M, Benoit V, Crespin M, Ghariani S . Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome. Am J Hum Genet. 2011; 90(1):119-24. PMC: 3257878. DOI: 10.1016/j.ajhg.2011.11.021. View

Marshall C, Chowdhury S, Taft R, Lebo M, Buchan J, Harrison S . Best practices for the analytical validation of clinical whole-genome sequencing intended for the diagnosis of germline disease. NPJ Genom Med. 2020; 5:47. PMC: 7585436. DOI: 10.1038/s41525-020-00154-9. View

10.

Adam M, Banka S, Bjornsson H, Bodamer O, Chudley A, Harris J . Kabuki syndrome: international consensus diagnostic criteria. J Med Genet. 2018; 56(2):89-95. DOI: 10.1136/jmedgenet-2018-105625. View

11.

Banka S, Veeramachaneni R, Reardon W, Howard E, Bunstone S, Ragge N . How genetically heterogeneous is Kabuki syndrome?: MLL2 testing in 116 patients, review and analyses of mutation and phenotypic spectrum. Eur J Hum Genet. 2011; 20(4):381-8. PMC: 3306863. DOI: 10.1038/ejhg.2011.220. View

12.

Gambin T, Akdemir Z, Yuan B, Gu S, Chiang T, Carvalho C . Homozygous and hemizygous CNV detection from exome sequencing data in a Mendelian disease cohort. Nucleic Acids Res. 2016; 45(4):1633-1648. PMC: 5389578. DOI: 10.1093/nar/gkw1237. View

13.

Butcher D, Cytrynbaum C, Turinsky A, Siu M, Inbar-Feigenberg M, Mendoza-Londono R . CHARGE and Kabuki Syndromes: Gene-Specific DNA Methylation Signatures Identify Epigenetic Mechanisms Linking These Clinically Overlapping Conditions. Am J Hum Genet. 2017; 100(5):773-788. PMC: 5420353. DOI: 10.1016/j.ajhg.2017.04.004. View

14.

Niikawa N, Matsuura N, Fukushima Y, Ohsawa T, Kajii T . Kabuki make-up syndrome: a syndrome of mental retardation, unusual facies, large and protruding ears, and postnatal growth deficiency. J Pediatr. 1981; 99(4):565-9. DOI: 10.1016/s0022-3476(81)80255-7. View

15.

Aref-Eshghi E, Bend E, Hood R, Schenkel L, Carere D, Chakrabarti R . BAFopathies' DNA methylation epi-signatures demonstrate diagnostic utility and functional continuum of Coffin-Siris and Nicolaides-Baraitser syndromes. Nat Commun. 2018; 9(1):4885. PMC: 6244416. DOI: 10.1038/s41467-018-07193-y. View

16.

Rots D, Chater-Diehl E, Dingemans A, Goodman S, Siu M, Cytrynbaum C . Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature. Am J Hum Genet. 2021; 108(6):1053-1068. PMC: 8206150. DOI: 10.1016/j.ajhg.2021.04.008. View

17.

Miyake N, Mizuno S, Okamoto N, Ohashi H, Shiina M, Ogata K . KDM6A point mutations cause Kabuki syndrome. Hum Mutat. 2012; 34(1):108-10. DOI: 10.1002/humu.22229. View

18.

Kuroki Y, Suzuki Y, Chyo H, Hata A, Matsui I . A new malformation syndrome of long palpebral fissures, large ears, depressed nasal tip, and skeletal anomalies associated with postnatal dwarfism and mental retardation. J Pediatr. 1981; 99(4):570-3. DOI: 10.1016/s0022-3476(81)80256-9. View

19.

Bogershausen N, Wollnik B . Unmasking Kabuki syndrome. Clin Genet. 2012; 83(3):201-11. DOI: 10.1111/cge.12051. View

20.

Bogershausen N, Gatinois V, Riehmer V, Kayserili H, Becker J, Thoenes M . Mutation Update for Kabuki Syndrome Genes KMT2D and KDM6A and Further Delineation of X-Linked Kabuki Syndrome Subtype 2. Hum Mutat. 2016; 37(9):847-64. DOI: 10.1002/humu.23026. View