A PMM2-CDG caused by an A108V mutation associated with a heterozygous 70 kilobases deletion case report.
CDG
Deletion mutation
PMM2
PMM2-CDG
Whole genome sequencing
Journal
Italian journal of pediatrics
ISSN: 1824-7288
Titre abrégé: Ital J Pediatr
Pays: England
ID NLM: 101510759
Informations de publication
Date de publication:
11 Oct 2022
11 Oct 2022
Historique:
received:
07
01
2022
accepted:
27
08
2022
entrez:
11
10
2022
pubmed:
12
10
2022
medline:
14
10
2022
Statut:
epublish
Résumé
Congenital Disorders of Glycosylation (CDG) are a large group of inborn errors of metabolism with more than 140 different CDG types reported to date (1). The first characterized, PMM2-CDG, with an autosomal recessive transmission, is also the most frequent. The PMM2 gene encodes a phosphomannomutase. Here, a novel genetic variation causing PMM2-CDG is reported. CASE PRESENTATION: We report the case of a French child, from healthy and unrelated parents, presenting congenital ataxia with hypotonia, hyperlaxity, inverted nipples, as well as altered coagulation parameters and liver function. Transferrin isoelectrofocusing revealed a typical type I CDG profile. Direct Sanger sequencing and quantitative PCR of PMM2 revealed a unique and novel genotype. On one allele, the patient was heterozygote with a known missense variant NM_000303.3(PMM2):c.323C > T, p.Ala108Val in exon 4. On the second allele, whole genome sequencing (WGS) indicated the presence of a novel heterozygous 70 kb deletion. We report in the present paper the largest known heterozygous deletion of a PMM2 gene. The observation reveals the impact of a precise diagnostic on genetic counselling: by using WGS, an erroneous conclusion of homozygosity in the case of a relatively rare variant could be avoided, and an index patient with healthy and unrelated parents correctly identified.
Sections du résumé
BACKGROUND
BACKGROUND
Congenital Disorders of Glycosylation (CDG) are a large group of inborn errors of metabolism with more than 140 different CDG types reported to date (1). The first characterized, PMM2-CDG, with an autosomal recessive transmission, is also the most frequent. The PMM2 gene encodes a phosphomannomutase. Here, a novel genetic variation causing PMM2-CDG is reported. CASE PRESENTATION: We report the case of a French child, from healthy and unrelated parents, presenting congenital ataxia with hypotonia, hyperlaxity, inverted nipples, as well as altered coagulation parameters and liver function. Transferrin isoelectrofocusing revealed a typical type I CDG profile. Direct Sanger sequencing and quantitative PCR of PMM2 revealed a unique and novel genotype. On one allele, the patient was heterozygote with a known missense variant NM_000303.3(PMM2):c.323C > T, p.Ala108Val in exon 4. On the second allele, whole genome sequencing (WGS) indicated the presence of a novel heterozygous 70 kb deletion.
CONCLUSION
CONCLUSIONS
We report in the present paper the largest known heterozygous deletion of a PMM2 gene. The observation reveals the impact of a precise diagnostic on genetic counselling: by using WGS, an erroneous conclusion of homozygosity in the case of a relatively rare variant could be avoided, and an index patient with healthy and unrelated parents correctly identified.
Identifiants
pubmed: 36221102
doi: 10.1186/s13052-022-01355-x
pii: 10.1186/s13052-022-01355-x
pmc: PMC9552460
doi:
Substances chimiques
Transferrins
0
Phosphotransferases (Phosphomutases)
EC 5.4.2.-
Types de publication
Case Reports
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
178Subventions
Organisme : Agence Nationale de la Recherche
ID : 643578
Informations de copyright
© 2022. The Author(s).
Références
JIMD Rep. 2012;5:123-5
pubmed: 23430927
Hum Mutat. 2000 Nov;16(5):386-94
pubmed: 11058895
Mol Cell Biol. 2011 Jan;31(2):277-86
pubmed: 21078874
Hum Mutat. 2005 May;25(5):504-5
pubmed: 15844218
Acta Paediatr Scand Suppl. 1991;375:1-71
pubmed: 1720595
Am J Hum Genet. 1998 Mar;62(3):542-50
pubmed: 9497260
Pharmacol Toxicol. 1989 Apr;64(4):383-5
pubmed: 2748548
Eur J Hum Genet. 2000 May;8(5):367-71
pubmed: 10854097
Front Genet. 2021 Aug 10;12:719437
pubmed: 34447415
Glycoconj J. 1999 Nov;16(11):669-71
pubmed: 11003549
Nat Genet. 1997 May;16(1):88-92
pubmed: 9140401
Biochim Biophys Acta Gen Subj. 2021 Jan;1865(1):129751
pubmed: 32991969