A homozygous frame-shift variant in PROSER1 is associated with developmental delay, hypotonia, genitourinary malformations, and distinctive facial features.
DNA methylation
PROSER1
epigenetics
histone methylation
neurodevelopmental disorders
novel gene
Journal
Clinical genetics
ISSN: 1399-0004
Titre abrégé: Clin Genet
Pays: Denmark
ID NLM: 0253664
Informations de publication
Date de publication:
05 2022
05 2022
Historique:
revised:
22
02
2022
received:
17
01
2022
accepted:
23
02
2022
pubmed:
2
3
2022
medline:
7
5
2022
entrez:
1
3
2022
Statut:
ppublish
Résumé
We report four children from three related families who presented with a similar phenotype characterized by developmental delay, hypotonia, seizures, failure-to-thrive, strabismus, drooling, recurrent otitis media, hearing impairment, and genitourinary malformations. They also shared common facial features including arched eyebrows, prominent eyes, broad nasal bridge, low-hanging columella, open mouth, thick lower lip, protruding tongue, large low-set ears, and parietal bossing. Exome sequencing for affected individuals revealed a homozygous frame-shift variant, c.1833del; p.(Thr612Glnfs*22), in PROSER1 which encodes the proline and serine rich protein 1 (PROSER1). PROSER1 has recently been found to be part of the histone methyltransferases KMT2C/KMT2D complexes. PROSER1 stabilizes TET2, a member of the TET family of DNA demethylases which is involved in recruiting the enhancer-associated KMT2C/KMT2D complexes and mediating DNA demethylation, activating gene expression. Therefore, PROSER1 may play vital and potentially general roles in gene regulation, consistent with the wide phenotypic spectrum observed in the individuals presented here. The consistent phenotype, the loss-of-function predicted from the frame-shift, the co-segregation of the phenotype in our large pedigree, the vital role of PROSER1 in gene regulation, and the association of related genes with neurodevelopmental disorders argue for the loss of PROSER1 to be the cause for a novel recognizable syndrome.
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
565-570Informations de copyright
© 2022 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.
Références
Srivastava S, Love-Nichols JA, Dies KA, et al. Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders. Genet Med Off J Am Coll Med Genet. 2019;21(11):2413-2421.
Manickam K, McClain MR, Demmer LA, et al. Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genet Med Off J Am Coll Med Genet. 2021;23(11):2029-2037.
Wright CF, FitzPatrick DR, Firth HV. Paediatric genomics: diagnosing rare disease in children. Nat Rev Genet. 2018;19(5):253-268.
Monies D, Abouelhoda M, AlSayed M, et al. The landscape of genetic diseases in Saudi Arabia based on the first 1000 diagnostic panels and exomes. Hum Genet. 2017;136(8):921-939.
Beetz C, Ameziane N, Kdissa A, et al. VPS26C homozygous nonsense variant in two cousins with neurodevelopmental deficits, growth failure, skeletal abnormalities, and distinctive facial features. Clin Genet. 2020;97(4):644-648.
Bauer P, Kandaswamy KK, Weiss MER, et al. Development of an evidence-based algorithm that optimizes sensitivity and specificity in ES-based diagnostics of a clinically heterogeneous patient population. Genet Med Off J Am Coll Med Genet. 2019;21(1):53-61.
Wang X, Rosikiewicz W, Sedkov Y, et al. PROSER1 mediates TET2 O-GlcNAcylation to regulate DNA demethylation on UTX-dependent enhancers and CpG islands. Life Sci Alliance. 2022;5(1):e202101228.
Bjornsson HT. The Mendelian disorders of the epigenetic machinery. Genome Res. 2015 Oct;25(10):1473-1481.
Wang C, Lee JE, Lai B, et al. Enhancer priming by H3K4 methyltransferase MLL4 controls cell fate transition. Proc Natl Acad Sci USA. 2016;113(42):11871-11876.
Jones WD, Dafou D, McEntagart M, et al. De novo mutations in MLL cause Wiedemann-Steiner syndrome. Am J Hum Genet. 2012;91(2):358-364.
Zech M, Boesch S, Maier EM, et al. Haploinsufficiency of KMT2B, encoding the lysine-specific histone methyltransferase 2B, results in early-onset generalized dystonia. Am J Hum Genet. 2016;99(6):1377-1387.
Kleefstra T, Kramer JM, Neveling K, et al. Disruption of an EHMT1-associated chromatin-modification module causes intellectual disability. Am J Hum Genet. 2012;91(1):73-82.
Ng SB, Bigham AW, Buckingham KJ, et al. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat Genet. 2010;42(9):790-793.
Faundes V, Goh S, Akilapa R, et al. Clinical delineation, sex differences, and genotype-phenotype correlation in pathogenic KDM6A variants causing X-linked Kabuki syndrome type 2. Genet Med Off J Am Coll Med Genet. 2021;23(7):1202-1210.
Beck DB, Petracovici A, He C, et al. Delineation of a human Mendelian disorder of the DNA demethylation machinery: TET3 deficiency. Am J Hum Genet. 2020;106(2):234-245.