Gene Haploinsufficiency in Three Patients With Suspected KBG Syndrome

Overview

Journal Front Neurol

Specialty Neurology

Date 2020 Aug 15

PMID 32793091

Citations 8

Authors

Milena Crippa

Ilaria Bestetti

Silvia Maitz

Karin Weiss

Alice Spano

Maura Masciadri

Sarah Smithson

Lidia Larizza

Karen Low

Lior Cohen

Palma Finelli

Affiliations

Soon will be listed here.

Abstract

Mendelian disorders of the epigenetic machinery (MDEMs), also named chromatin modifying disorders, are a broad group of neurodevelopmental disorders, caused by mutations in functionally related chromatin genes. Mental retardation autosomal dominant 23 (MRD23) syndrome, due to gene mutations, falls into this group of disorders. KBG syndrome, caused by gene haploinsufficiency, is a chromatin related syndrome not formally belonging to this category. We performed high resolution array CGH and trio-based WES on three molecularly unsolved patients with an initial KBGS clinical diagnosis. A deletion of 116 kb partially involving and two frameshift variants in were identified in the patients. The clinical re-evaluation of the patients was consistent with the molecular findings, though still compatible with KBGS due to overlapping phenotypic features of KBGS and MRD23. Careful detailed expert phenotyping ascertained some facial and physical features that were consistent with MRD23 rather than KBGS. Our results provide further examples that loss-of-function pathogenic variants in genes encoding factors shaping the epigenetic landscape, lead to a wide phenotypic range with significant clinical overlap. We recommend that clinicians consider gene haploinsufficiency in the differential diagnosis of KBGS. Due to overlap of clinical features, careful and detailed phenotyping is important and a large gene panel approach is recommended in the diagnostic workup of patients with a clinical suspicion of KBGS.

Citing Articles

ANKRD11 binding to cohesin suggests a connection between KBG syndrome and Cornelia de Lange syndrome.

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A study on genotypes and phenotypes of short stature caused by epigenetic modification gene variants.

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Epigenetic regulation of craniofacial development and disease.

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Structure, activity and function of the lysine methyltransferase SETD5.

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References

Zhang A, Li C, Chen J . Characterization of transcriptional regulatory domains of ankyrin repeat cofactor-1. Biochem Biophys Res Commun. 2007; 358(4):1034-40. PMC: 1950474. DOI: 10.1016/j.bbrc.2007.05.017. View

Parenti I, Gervasini C, Pozojevic J, Graul-Neumann L, Azzollini J, Braunholz D . Broadening of cohesinopathies: exome sequencing identifies mutations in ANKRD11 in two patients with Cornelia de Lange-overlapping phenotype. Clin Genet. 2015; 89(1):74-81. DOI: 10.1111/cge.12564. View

Sirmaci A, Spiliopoulos M, Brancati F, Powell E, Duman D, Abrams A . Mutations in ANKRD11 cause KBG syndrome, characterized by intellectual disability, skeletal malformations, and macrodontia. Am J Hum Genet. 2011; 89(2):289-94. PMC: 3155157. DOI: 10.1016/j.ajhg.2011.06.007. View

Szczaluba K, Brzezinska M, Kot J, Rydzanicz M, Walczak A, Stawinski P . SETD5 loss-of-function mutation as a likely cause of a familial syndromic intellectual disability with variable phenotypic expression. Am J Med Genet A. 2016; 170(9):2322-7. DOI: 10.1002/ajmg.a.37832. View

Izumi K . Disorders of Transcriptional Regulation: An Emerging Category of Multiple Malformation Syndromes. Mol Syndromol. 2016; 7(5):262-273. PMC: 5109993. DOI: 10.1159/000448747. View

Kobayashi Y, Tohyama J, Kato M, Akasaka N, Magara S, Kawashima H . High prevalence of genetic alterations in early-onset epileptic encephalopathies associated with infantile movement disorders. Brain Dev. 2015; 38(3):285-92. DOI: 10.1016/j.braindev.2015.09.011. View

Green C, Willoughby J, Balasubramanian M . De novo SETD5 loss-of-function variant as a cause for intellectual disability in a 10-year old boy with an aberrant blind ending bronchus. Am J Med Genet A. 2017; 173(12):3165-3171. DOI: 10.1002/ajmg.a.38461. View

Miller D, Adam M, Aradhya S, Biesecker L, Brothman A, Carter N . Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010; 86(5):749-64. PMC: 2869000. DOI: 10.1016/j.ajhg.2010.04.006. View

Lek M, Karczewski K, Minikel E, Samocha K, Banks E, Fennell T . Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016; 536(7616):285-91. PMC: 5018207. DOI: 10.1038/nature19057. View

10.

Fahrner J, Bjornsson H . Mendelian disorders of the epigenetic machinery: postnatal malleability and therapeutic prospects. Hum Mol Genet. 2019; 28(R2):R254-R264. PMC: 6872430. DOI: 10.1093/hmg/ddz174. View

11.

Parenti I, Teresa-Rodrigo M, Pozojevic J, Gil S, Bader I, Braunholz D . Mutations in chromatin regulators functionally link Cornelia de Lange syndrome and clinically overlapping phenotypes. Hum Genet. 2017; 136(3):307-320. DOI: 10.1007/s00439-017-1758-y. View

12.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J . 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(5):405-24. PMC: 4544753. DOI: 10.1038/gim.2015.30. View

13.

Miyatake S, Okamoto N, Stark Z, Nabetani M, Tsurusaki Y, Nakashima M . ANKRD11 variants cause variable clinical features associated with KBG syndrome and Coffin-Siris-like syndrome. J Hum Genet. 2017; 62(8):741-746. PMC: 5537415. DOI: 10.1038/jhg.2017.24. View

14.

Deliu E, Arecco N, Morandell J, Dotter C, Contreras X, Girardot C . Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition. Nat Neurosci. 2018; 21(12):1717-1727. DOI: 10.1038/s41593-018-0266-2. View

15.

Powis Z, Farwell Hagman K, Mroske C, McWalter K, Cohen J, Colombo R . Expansion and further delineation of the SETD5 phenotype leading to global developmental delay, variable dysmorphic features, and reduced penetrance. Clin Genet. 2017; 93(4):752-761. DOI: 10.1111/cge.13132. View

16.

Kearney H, Thorland E, Brown K, Quintero-Rivera F, South S . American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants. Genet Med. 2011; 13(7):680-5. DOI: 10.1097/GIM.0b013e3182217a3a. View

17.

Aoi H, Mizuguchi T, Ceroni J, Kim V, Furquim I, Honjo R . Comprehensive genetic analysis of 57 families with clinically suspected Cornelia de Lange syndrome. J Hum Genet. 2019; 64(10):967-978. DOI: 10.1038/s10038-019-0643-z. View

18.

Li H, Durbin R . Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics. 2010; 26(5):589-95. PMC: 2828108. DOI: 10.1093/bioinformatics/btp698. View

19.

Herrmann J, PALLISTER P, Tiddy W, Opitz J . The KBG syndrome-a syndrome of short stature, characteristic facies, mental retardation, macrodontia and skeletal anomalies. Birth Defects Orig Artic Ser. 1975; 11(5):7-18. View

20.

Yang H, Wang K . Genomic variant annotation and prioritization with ANNOVAR and wANNOVAR. Nat Protoc. 2015; 10(10):1556-66. PMC: 4718734. DOI: 10.1038/nprot.2015.105. View