(National Laboratories Excellence program (under the National Tumorbiology Laboratory
project))
(FK_131916)
(EFOP- 3.6.3-VEKOP-16–2017-00009)
(ÚNKP-20-3-I-SE-24)
(Bolyai Research Fellowship of the Hungarian Academy of Sciences)
(ÚNKP-22–5-SE-1.)
Carney complex (CNC) is an ultrarare disorder causing cutaneous and cardiac myxomas,
primary pigmented nodular adrenocortical disease, hypophyseal adenoma, and gonadal
tumours. Genetic alterations are often missed under routine genetic testing. Pathogenic
variants in PRKAR1A are identified in most cases, while large exonic or chromosomal
deletions have only been reported in a few cases. Our aim was to identify the causal
genetic alteration in our kindred with a clinical diagnosis of CNC and prove its pathogenic
role by functional investigation. Targeted testing of PRKAR1A gene, whole exome and
whole genome sequencing (WGS) were performed in the proband, one clinically affected
and one unaffected relative. WGS identified a novel, large, 10,662 bp (10.6 kbp; LRG_514t1:c.-10403_-7
+ 265del; hg19, chr17:g.66498293_66508954del) deletion in the promoter of PRKAR1A
in heterozygous form in the affected family members. The exact breakpoints and the
increased enzyme activity in deletion carriers compared to wild type carrier were
proved. Segregation analysis and functional evaluation of PKA activity confirmed the
pathogenic role of this alteration. A novel deletion upstream of the PRKAR1A gene
was proved to be the cause of CNC. Our study underlines the need for WGS in molecular
genetic testing of patients with monogenic disorders where conventional genetic analysis
fails.
