ATAD3A-related pontocerebellar hypoplasia: new patients and insights into phenotypic variability

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00064165%3A_____%2F23%3A10465251" target="_blank" >RIV/00064165:_____/23:10465251 - isvavai.cz</a>

Alternative codes found

RIV/00216208:11110/23:10465251

Result on the web

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=K1kt-p.1Oq" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=K1kt-p.1Oq</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1186/s13023-023-02689-3" target="_blank" >10.1186/s13023-023-02689-3</a>

Result language

angličtina

Original language name

ATAD3A-related pontocerebellar hypoplasia: new patients and insights into phenotypic variability

Original language description

Background: Pathogenic variants in the ATAD3A gene lead to a heterogenous clinical picture and severity ranging from recessive neonatal-lethal pontocerebellar hypoplasia through milder dominant Harel-Yoon syndrome up to, again, neonatal-lethal but dominant cardiomyopathy. The genetic diagnostics of ATAD3A-related disorders is also challenging due to three paralogous genes in the ATAD3 locus, making it a difficult target for both sequencing and CNV analyses. Results: Here we report four individuals from two families with compound heterozygous p.Leu77Val and exon 3-4 deletion in the ATAD3A gene. One of these patients was characterized as having combined OXPHOS deficiency based on decreased complex IV activities, decreased complex IV, I, and V holoenzyme content, as well as decreased levels of COX2 and ATP5A subunits and decreased rate of mitochondrial proteosynthesis. All four reported patients shared a strikingly similar clinical picture to a previously reported patient with the p.Leu77Val variant in combination with a null allele. They presented with a less severe course of the disease and a longer lifespan than in the case of biallelic loss-of-function variants. This consistency of the phenotype in otherwise clinically heterogenous disorder led us to the hypothesis that the severity of the phenotype could depend on the severity of variant impact. To follow this rationale, we reviewed the published cases and sorted the recessive variants according to their impact predicted by their type and the severity of the disease in the patients. Conclusion: The clinical picture and severity of ATAD3A-related disorders are homogenous in patients sharing the same combinations of variants. This knowledge enables deduction of variant impact severity based on known cases and allows more accurate prognosis estimation, as well as a better understanding of the ATAD3A function.

Czech name

—

Czech description

—

Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30101 - Human genetics

Project

<a href="/en/project/LM2018132" target="_blank" >LM2018132: The National Center for Medical Genomic</a><br>

Continuities

V - Vyzkumna aktivita podporovana z jinych verejnych zdroju

Publication year

2023

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Orphanet Journal of Rare Diseases

ISSN

1750-1172

e-ISSN

1750-1172

Volume of the periodical

18

Issue of the periodical within the volume

1

Country of publishing house

GB - UNITED KINGDOM

Number of pages

12

Pages from-to

92

UT code for WoS article

000974073900001

EID of the result in the Scopus database

2-s2.0-85153687498