Estimation of minimal disease prevalence from population genomic data: Application to primary familial brain calcification

Abstract

Primary Familial Brain Calcification (PFBC) is a rare calcifying disorder of the brain with autosomal dominant inheritance, of unknown prevalence. Four causal genes have been identified so far: SLC20A2, PDGFB, PDGFRB, and XPR1, with pathogenic, probably pathogenic or missense variants of unknown significance found in 27.7% probands in the French PFBC series. Estimating PFBC prevalence from a clinical input is arduous due to a large diversity of symptoms and ages of onset and to incomplete clinical penetrance. Abnormal calcifications on CT scan can be used as a reliable diagnostic biomarker whatever the clinical status, but differential diagnoses should be ruled out including the challenging exclusion of common basal ganglia calcifications. Our primary aim was to estimate the minimal prevalence of PFBC due to a variant in one of the known genes. We extracted variants from the four known genes present in the gnomAD database gathering genomic data from 138,632 individuals. We interpreted all variants based on their predicted effect, their frequency, and previous studies on PFBC patients. Using the most conservative estimate, the minimal prevalence of PFBC related to a variant in one of the four known genes was 4.5 p. 10,000 (95%CI [3.4-5.5] p. 10,000). We then used variant detection rates in patients to extrapolate an overall minimal prevalence of PFBC to 2.1 p. 1,000 (95%CI [1.9-2.4] p. 1,000). The population-based genomic analysis indicates that PFBC is not an exceptionally rare disorder, still underestimated and underdiagnosed.

Ossified blood vessels in primary familial brain calcification elicit a neurotoxic astrocyte response

“…Recessively inherited PFBC is associated with mutations in myogenesis regulating glycosidase ( MYORG ) (Yao et al , 2018). The estimated minimal prevalence is 4.5 per 10 000, suggesting that PFBC is not a rare disorder and is underdiagnosed (Nicolas et al , 2018). The clinical penetration of PFBC is incomplete and heterogeneous comprising of psychiatric signs (e.g.…”

MYORG -related disease is associated with central pontine calcifications and atypical parkinsonism

“…Primary familial brain calcification (PFBC) is a genetic neurodegenerative condition characterized by calcium deposition in the basal ganglia and other brain regions usually presenting with a combination of movement disorders, migraine, psychiatric, and cognitive impairment. The exact prevalence of PFBC is unknown, but population-based genomic analysis indicates that it is underestimated and underdiagnosed, 1 with a molecular diagnosis achieved in only up to 50% of PFBC cases. 2 The pathogenesis of PFBC involves calcium and phosphate homeostasis via mutations in SLC20A2 (OMIM: 158378) and XPR1 (OMIM: 605237) and endothelial integrity and function affecting the blood-brain barrier via mutations in PDGFB (OMIM: 190040) and PDGFRB (OMIM: 173410).…”

Fahr’s Disease: A Differential to Be Considered for Various Neuropsychiatric Presentations

“…However, with the most conservative estimations, the minimal prevalence of variants of known genes is 4.5 p. 10,000 (95%CI [3.4–5.5] p. 10,000). Population genomic analysis reveals that this is not a very rare disease, and it has been underestimated and underdiagnosed so far [ 3 ].…”

“…Fahr’s disease is considered to be one of the rare neurological diseases that present with a wide array of presentations, including movement disorders and psychiatric manifestations [ 1 ].The disease was previously described by the German neurologist Fahr in the early 1930s [ 2 ]. Since then, many scientists have been trying to develop a better understanding of this rare disease [ 3 ]. There is strong evidence to suggest that the disease is largely hereditary, with a possible autosomal dominant mode of inheritance.…”