Pattern Recognition of Common Multiple Congenital Malformation Syndromes with Underlying Chromatinopathy

Abstract

Chromatinopathy is an emerging category of multiple malformation syndromes caused by disruption in global transcriptional regulation with imbalances in the chromatin states (i.e., open or closed chromatin). These syndromes are caused by pathogenic variants in genes coding for the writers, erasers, readers, and remodelers of the epigenetic machinery. Majority of these disorders (93%) show neurological dysfunction in the form of intellectual disability. Other overlapping features are growth abnormalities, limb deformities, and immune dysfunction. In this study, we describe a series of children with six common chromatinopathy syndromes with an aim to develop pattern recognition of this emerging category of multiple malformation syndromes

Keywords

chromatinopathy - epigenetic - multiple malformation syndromes

Ethical Approval

This study was approved by Institute Ethics Committee. Informed consent was taken from patient families for publishing photographs and clinical details.

Publication History

Received: 17 August 2021

Accepted: 07 March 2022

Article published online:
27 June 2022

• References

• 1 Fahrner JA, Bjornsson HT. Mendelian disorders of the epigenetic machinery: tipping the balance of chromatin states. Annu Rev Genomics Hum Genet 2014; 15: 269-293
• 2 Fahrner JA, Bjornsson HT. Mendelian disorders of the epigenetic machinery: postnatal malleability and therapeutic prospects. Hum Mol Genet 2019;28(R2):R254–R264 10.1093/hmg/ddz174 Erratum in: Hum Mol Genet. 2020 Mar 27;29(5):876. PMID: 31595951; PMCID: PMC6872430
• 3 Richards S, Aziz N, Bale S. et al; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17 (05) 405-424
• 4 Kline AD, Moss JF, Selicorni A. et al. Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement. Nat Rev Genet 2018; 19 (10) 649-666
• 5 Izumi K. Disorders of transcriptional regulation: an emerging category of multiple malformation syndromes. Mol Syndromol 2016; 7 (05) 262-273
• 6 Low K, Ashraf T, Canham N. et al; DDD Study. Clinical and genetic aspects of KBG syndrome. Am J Med Genet A 2016; 170 (11) 2835-2846
• 7 Skjei KL, Martin MM, Slavotinek AM. KBG syndrome: report of twins, neurological characteristics, and delineation of diagnostic criteria. Am J Med Genet A 2007; 143A [phone]
• 8 Parenti I, Teresa-Rodrigo ME, Pozojevic J. et al. Mutations in chromatin regulators functionally link Cornelia de Lange syndrome and clinically overlapping phenotypes. Hum Genet 2017; 136 (03) 307-320
• 9 Adam MP, Banka S, Bjornsson HT. et al; Kabuki Syndrome Medical Advisory Board. Kabuki syndrome: international consensus diagnostic criteria. J Med Genet 2019; 56 (02) 89-95
• 10 Margot H, Boursier G, Duflos C. et al. Immunopathological manifestations in Kabuki syndrome: a registry study of 177 individuals. Genet Med 2020; 22 (01) 181-188
• 11 Van Laarhoven PM, Neitzel LR, Quintana AM. et al. Kabuki syndrome genes KMT2D and KDM6A: functional analyses demonstrate critical roles in craniofacial, heart and brain development. Hum Mol Genet 2015; 24 (15) 4443-4453
• 12 Stellacci E, Onesimo R, Bruselles A. et al. Congenital immunodeficiency in an individual with Wiedemann-Steiner syndrome due to a novel missense mutation in KMT2A. Am J Med Genet A 2016; 170 (09) 2389-2393
• 13 Di Fede E, Massa V, Augello B, Squeo G, Scarano E, Perri AM, Fischetto R, Causio FA, Zampino G, Piccione M, Curridori E, Mazza T, Castellana S, Larizza L, Ghelma F, Colombo EA, Gandini MC, Castori M, Merla G, Milani D, Gervasini C. Expanding the phenotype associated to KMT2A variants: overlapping clinical signs between Wiedemann-Steiner and Rubinstein-Taybi syndromes. Eur J Hum Genet 2021 Jan;29(01):88–98. doi: 10.1038/s41431-020-0679-8. Epub 2020 Jul 8. PMID: 32641752; PMCID: PMC7852672
• 14 Bramswig NC, Lüdecke HJ, Alanay Y. et al. Exome sequencing unravels unexpected differential diagnoses in individuals with the tentative diagnosis of Coffin-Siris and Nicolaides-Baraitser syndromes. Hum Genet 2015; 134 (06) 553-568
• 15 Yuan B, Pehlivan D, Karaca E. et al. Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes. J Clin Invest 2015; 125 (02) 636-651
• 16 Parenti I, Gervasini C, Pozojevic J, Graul-Neumann L, Azzollini J, Braunholz D, Watrin E, Wendt KS, Cereda A, Cittaro D, Gillessen-Kaesbach G, Lazarevic D, Mariani M, Russo S, Werner R, Krawitz P, Larizza L, Selicorni A, Kaiser FJ. Broadening of cohesinopathies: exome sequencing identifies mutations in ANKRD11 in two patients with Cornelia de Lange-overlapping phenotype. Clin Genet 2016 Jan;89(01):74–81. doi: 10.1111/cge.12564. Epub 2015 Feb 25. PMID: 25652421
• 17 Sobreira N, Brucato M, Zhang L. et al. Patients with a Kabuki syndrome phenotype demonstrate DNA methylation abnormalities. Eur J Hum Genet 2017; 25 (12) 1335-1344
• 18 Negri G, Magini P, Milani D. et al. Exploring by whole exome sequencing patients with initial diagnosis of Rubinstein-Taybi syndrome: the interconnections of epigenetic machinery disorders. Hum Genet 2019; 138 (03) 257-269
• 19 Woods SA, Robinson HB, Kohler LJ, Agamanolis D, Sterbenz G, Khalifa M. Exome sequencing identifies a novel EP300 frame shift mutation in a patient with features that overlap Cornelia de Lange syndrome. Am J Med Genet A 2014; 164A [phone]
• 20 Cucco F, Sarogni P, Rossato S. et al. Pathogenic variants in EP300 and ANKRD11 in patients with phenotypes overlapping Cornelia de Lange syndrome. Am J Med Genet A 2020; 182 (07) 1690-1696
• 21 Miyatake S, Okamoto N, Stark Z. et al. ANKRD11 variants cause variable clinical features associated with KBG syndrome and Coffin-Siris-like syndrome. J Hum Genet 2017; 62 (08) 741-746
• 22 Avagliano L, Parenti I, Grazioli P. et al. Chromatinopathies: a focus on Cornelia de Lange syndrome. Clin Genet 2020; 97 (01) 3-11
• 23 Squeo GM, Augello B, Massa V. et al. Customised next-generation sequencing multigene panel to screen a large cohort of individuals with chromatin-related disorder. J Med Genet 2020; 57 (11) 760-768
• 24 Aref-Eshghi E, Bend EG, Colaiacovo S. et al. Diagnostic utility of genome-wide DNA methylation testing in genetically unsolved individuals with suspected hereditary conditions. Am J Hum Genet 2019; 104 (04) 685-700
• 25 Alarcón JM, Malleret G, Touzani K. et al. Chromatin acetylation, memory, and LTP are impaired in CBP+/- mice: a model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration. Neuron 2004; 42 (06) 947-959 [PubMed: 15207239]
• 26 Korzus E, Rosenfeld MG, Mayford M. CBP histone acetyltransferase activity is a critical component of memory consolidation. Neuron 2004; 42 (06) 961-972 [PubMed: 15207240]
• 27 Bjornsson HT, Benjamin JS, Zhang L. et al. Histone deacetylase inhibition rescues structural and functional brain deficits in a mouse model of Kabuki syndrome. Sci Transl Med 2014; 6 (256) 256ra135
• 28 Lim DA, Huang YC, Swigut T, Mirick AL, Garcia-Verdugo JM, Wysocka J. et al. Chromatin remodelling factor Mll1 is essential for neurogenesis from postnatal neural stem cells. Nature 2009; 458: 529-533
• 29 Raab JR, Resnick S, Magnuson T. Genome-wide transcriptional regulation mediated by biochemically distinct SWI/SNF complexes. PLoS Genet 11:e1005748 (2015)
• 30 Bjornsson HT. The Mendelian disorders of the epigenetic machinery. Genome Res 2015 Oct;25(10):1473-81. doi: 10.1101/gr.190629.115. PMID: 26430157; PMCID: PMC4579332