Epigenomic Newborn Screening for Conditions with Intellectual Disability and Autistic Features in Australian Newborns

Overview

Journal Epigenomics

Specialty Genetics

Date 2024 Oct 4

PMID 39365098

Authors

Mohammed Alshawsh

Melissa Wake

Jozef Gecz

Mark Corbett

Richard Saffery

James Pitt

Ronda Greaves

Katrina Williams

Michael Field

Jeanie Cheong

Minh Bui

Sheena Arora

Simon Sadedin

Sebastian Lunke

Meg Wall

David J Amor

David E Godler

Affiliations

Soon will be listed here.

Abstract

This study describes a protocol to assess a novel workflow called Epi-Genomic Newborn Screening (EpiGNs) on 100,000 infants from the state of Victoria, Australia. The workflow uses a first-tier screening approach called methylation-specific quantitative melt analysis (MS-QMA), followed by second and third tier testing including targeted methylation and copy number variation analyzes with droplet digital PCR, EpiTYPER system and low-coverage whole genome sequencing. EpiGNs utilizes only two 3.2 mm newborn blood spot punches to screen for genetic conditions, including fragile X syndrome, Prader-Willi syndrome, Angelman syndrome, Dup15q syndrome and sex chromosome aneuploidies. The program aims to: identify clinically actionable methylation screening thresholds for the first-tier screen and estimate prevalence for the conditions screened.

References

Inaba Y, Schwartz C, Bui Q, Li X, Skinner C, Field M . Early detection of fragile X syndrome: applications of a novel approach for improved quantitative methylation analysis in venous blood and newborn blood spots. Clin Chem. 2014; 60(7):963-73. DOI: 10.1373/clinchem.2013.217331. View

Kraan C, Baker E, Arpone M, Bui M, Ling L, Gamage D . DNA Methylation at Birth Predicts Intellectual Functioning and Autism Features in Children with Fragile X Syndrome. Int J Mol Sci. 2020; 21(20). PMC: 7589848. DOI: 10.3390/ijms21207735. View

Blumling A, Martyn K, Talboy A, Close S . Rare sex chromosome variation 48,XXYY: An integrative review. Am J Med Genet C Semin Med Genet. 2020; 184(2):386-403. DOI: 10.1002/ajmg.c.31789. View

Kimonis V, Tamura R, Gold J, Patel N, Surampalli A, Manazir J . Early Diagnosis in Prader-Willi Syndrome Reduces Obesity and Associated Co-Morbidities. Genes (Basel). 2019; 10(11). PMC: 6896038. DOI: 10.3390/genes10110898. View

Tartaglia N, Ayari N, Howell S, DEpagnier C, Zeitler P . 48,XXYY, 48,XXXY and 49,XXXXY syndromes: not just variants of Klinefelter syndrome. Acta Paediatr. 2011; 100(6):851-60. PMC: 3314712. DOI: 10.1111/j.1651-2227.2011.02235.x. View

Riggan K, Gross B, Close S, Weinberg A, Allyse M . Prenatal Genetic Diagnosis of a Sex Chromosome Aneuploidy: Parent Experiences. J Genet Couns. 2021; 30(5):1407-1417. DOI: 10.1002/jgc4.1407. View

Marwaha S, Knowles J, Ashley E . A guide for the diagnosis of rare and undiagnosed disease: beyond the exome. Genome Med. 2022; 14(1):23. PMC: 8883622. DOI: 10.1186/s13073-022-01026-w. View

Elgersma Y, Sonzogni M . UBE3A reinstatement as a disease-modifying therapy for Angelman syndrome. Dev Med Child Neurol. 2021; 63(7):802-807. PMC: 8248324. DOI: 10.1111/dmcn.14831. View

Murdock D, Donovan F, Chandrasekharappa S, Banks N, Bondy C, Muenke M . Whole-Exome Sequencing for Diagnosis of Turner Syndrome: Toward Next-Generation Sequencing and Newborn Screening. J Clin Endocrinol Metab. 2017; 102(5):1529-1537. PMC: 5443329. DOI: 10.1210/jc.2016-3414. View

10.

Ibanez K, Polke J, Hagelstrom R, Dolzhenko E, Pasko D, Thomas E . Whole genome sequencing for the diagnosis of neurological repeat expansion disorders in the UK: a retrospective diagnostic accuracy and prospective clinical validation study. Lancet Neurol. 2022; 21(3):234-245. PMC: 8850201. DOI: 10.1016/S1474-4422(21)00462-2. View

11.

Dean D, Agarwal S, Muthuswamy S . Fragile X molecular investigation and genetic counseling of intellectual disability/developmental delay patients in an Indian scenario. Expert Rev Mol Diagn. 2019; 19(7):641-649. DOI: 10.1080/14737159.2019.1622416. View

12.

Han J, Lee I . Genetic tests by next-generation sequencing in children with developmental delay and/or intellectual disability. Clin Exp Pediatr. 2020; 63(6):195-202. PMC: 7303420. DOI: 10.3345/kjp.2019.00808. View

13.

Bailey Jr D, Porter K, Andrews S, Raspa M, Gwaltney A, Peay H . Expert Evaluation of Strategies to Modernize Newborn Screening in the United States. JAMA Netw Open. 2021; 4(12):e2140998. PMC: 8717100. DOI: 10.1001/jamanetworkopen.2021.40998. View

14.

Lee J, Hwang H, Kim S, Kim K, Choi J, Woo M . Chromosomal Microarray With Clinical Diagnostic Utility in Children With Developmental Delay or Intellectual Disability. Ann Lab Med. 2018; 38(5):473-480. PMC: 5973923. DOI: 10.3343/alm.2018.38.5.473. View

15.

Kalsner L, Chamberlain S . Prader-Willi, Angelman, and 15q11-q13 Duplication Syndromes. Pediatr Clin North Am. 2015; 62(3):587-606. PMC: 4449422. DOI: 10.1016/j.pcl.2015.03.004. View

16.

Downie L, Bouffler S, Amor D, Christodoulou J, Yeung A, Horton A . Gene selection for genomic newborn screening: Moving toward consensus?. Genet Med. 2024; 26(5):101077. DOI: 10.1016/j.gim.2024.101077. View

17.

Ar Rochmah M, Harahap N, Niba E, Nakanishi K, Awano H, Morioka I . Genetic screening of spinal muscular atrophy using a real-time modified COP-PCR technique with dried blood-spot DNA. Brain Dev. 2017; 39(9):774-782. DOI: 10.1016/j.braindev.2017.04.015. View

18.

Hensel C, Vanzo R, Martin M, Ling L, Aliaga S, Bui M . Abnormally Methylated FMR1 in Absence of a Detectable Full Mutation in a U.S.A Patient Cohort Referred for Fragile X Testing. Sci Rep. 2019; 9(1):15315. PMC: 6814816. DOI: 10.1038/s41598-019-51618-7. View

19.

Baker E, Merton C, Tan W, Dudding-Byth T, Godler D, Sadhwani A . Methylation analysis and developmental profile of two individuals with Angelman syndrome due to mosaic imprinting defects. Eur J Med Genet. 2022; 65(4):104456. PMC: 9800002. DOI: 10.1016/j.ejmg.2022.104456. View

20.

Krupp D, Barnard R, Duffourd Y, Evans S, Mulqueen R, Bernier R . Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder. Am J Hum Genet. 2017; 101(3):369-390. PMC: 5590950. DOI: 10.1016/j.ajhg.2017.07.016. View