Triple diagnosis of Wiedemann-Steiner, Waardenburg and DLG3-related intellectual disability association found by WES: A case report.
Abnormalities, Multiple
/ diagnosis
Beckwith-Wiedemann Syndrome
Child
Genetic Predisposition to Disease
Histone-Lysine N-Methyltransferase
/ genetics
Humans
Intellectual Disability
/ diagnosis
Male
Molecular Diagnostic Techniques
Mutation
Myeloid-Lymphoid Leukemia Protein
/ genetics
Nuclear Proteins
/ genetics
PAX3 Transcription Factor
/ genetics
Transcription Factors
/ genetics
Waardenburg Syndrome
/ diagnosis
Exome Sequencing
direct sequencing
gene expression
molecular genetics
neurology
Journal
The journal of gene medicine
ISSN: 1521-2254
Titre abrégé: J Gene Med
Pays: England
ID NLM: 9815764
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
08
10
2019
revised:
19
02
2020
accepted:
21
03
2020
pubmed:
5
4
2020
medline:
7
8
2021
entrez:
5
4
2020
Statut:
ppublish
Résumé
The development of whole-exome sequencing (WES) and whole-genome sequencing (WGS) for clinical purposes now allows the identification of multiple pathogenic variants in patients with a rare disease. This occurs even when a single causative gene was initially suspected. We report the case of an 8-year-old patient with global developmental delays and dysmorphic features, with a possibly pathogenic variant in three distinct genes. Trio-based exome sequencing was performed by IntegraGen SA (Evry, France), on an Illumina HiSeq4000 (Illumina, San Diego, CA, USA). Sanger sequencing was performed to confirm the variants that were found. WES showed the presence of three possibly deleterious variants: KMT2A: c.9068delA;p.Gln3023Argfs*3 de novo, PAX3: c.530C>G;p.Ala177Gly de novo and DLG3: c.127delG;p.Asp43Metfs*22 hemizygous inherited from the mother. KMT2A pathogenic variants are involved in Wiedemann-Steiner syndrome, and PAX3 is the gene responsible for Waardenburg syndrome. DLG3 variants have been described in a non-syndromic X-related intellectual disability. Considering the dysmorphic features and intellectual disability presented by this patient, these three variants were imputed as pathogenic and their association was considered responsible for his phenotype. Dual molecular diagnoses have already been found by WES in several cohorts with an average of diagnostic yield of 7%. This case demonstrates and reminds us of the importance of analyzing exomes rigorously and exhaustively because, in some cases (< 10%), it can explain superimposed traits or blended phenotypes.
Sections du résumé
BACKGROUND
The development of whole-exome sequencing (WES) and whole-genome sequencing (WGS) for clinical purposes now allows the identification of multiple pathogenic variants in patients with a rare disease. This occurs even when a single causative gene was initially suspected. We report the case of an 8-year-old patient with global developmental delays and dysmorphic features, with a possibly pathogenic variant in three distinct genes.
METHODS
Trio-based exome sequencing was performed by IntegraGen SA (Evry, France), on an Illumina HiSeq4000 (Illumina, San Diego, CA, USA). Sanger sequencing was performed to confirm the variants that were found.
RESULTS
WES showed the presence of three possibly deleterious variants: KMT2A: c.9068delA;p.Gln3023Argfs*3 de novo, PAX3: c.530C>G;p.Ala177Gly de novo and DLG3: c.127delG;p.Asp43Metfs*22 hemizygous inherited from the mother. KMT2A pathogenic variants are involved in Wiedemann-Steiner syndrome, and PAX3 is the gene responsible for Waardenburg syndrome. DLG3 variants have been described in a non-syndromic X-related intellectual disability.
CONCLUSIONS
Considering the dysmorphic features and intellectual disability presented by this patient, these three variants were imputed as pathogenic and their association was considered responsible for his phenotype. Dual molecular diagnoses have already been found by WES in several cohorts with an average of diagnostic yield of 7%. This case demonstrates and reminds us of the importance of analyzing exomes rigorously and exhaustively because, in some cases (< 10%), it can explain superimposed traits or blended phenotypes.
Substances chimiques
DLG3 protein, human
0
KMT2A protein, human
0
Nuclear Proteins
0
PAX3 Transcription Factor
0
PAX3 protein, human
0
Transcription Factors
0
Myeloid-Lymphoid Leukemia Protein
149025-06-9
Histone-Lysine N-Methyltransferase
EC 2.1.1.43
Types de publication
Case Reports
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e3197Informations de copyright
© 2020 John Wiley & Sons, Ltd.
Références
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