Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant pachygyria in the Finnish population

Abstract

Intellectual disability (ID), megalencephaly, frontal predominant pachygyria, and seizures, previously called "thin" lissencephaly, are reported to be caused by recessive variants in CRADD. Among five families of different ethnicities identified, one homozygous missense variant, c.509G>A p.(Arg170His), was of Finnish ancestry. Here we report on the phenotypic variability associated for this potential CRADD founder variant in 22 Finnish individuals. Exome sequencing was used to identify candidate genes in Finnish patients presenting with ID. Targeted Sanger sequencing and restriction enzyme analysis were applied to screen for the c.509G>A CRADD variant in cohorts from Finland. Detailed phenotyping and genealogical studies were performed. Twenty two patients were identified with the c.509G>A p.(Arg170His) homozygous variant in CRADD. The majority of the ancestors originated from Northeastern Finland indicating a founder effect. The hallmark of the disease is frontotemporal predominant pachygyria with mild cortical thickening. All patients show ID of variable severity. Aggressive behavior was found in nearly half of the patients, EEG abnormalities in five patients and megalencephaly in three patients. This study provides detailed data about the phenotypic spectrum of patients with lissencephaly due to a CRADD variant that affects function. High inter-and intrafamilial phenotypic heterogeneity was identified in patients with pachygyria caused by the homozygous CRADD founder variant. The phenotype variability suggests that additional genetic and/or environmental factors play a role in the clinical presentation. Since frontotemporal pachygyria is the hallmark of the disease, brain imaging studies are essential to support the molecular diagnosis for individuals with ID and a CRADD variant.

Exome sequencing reveals predominantly de novo variants in disorders with intellectual disability (ID) in the founder population of Finland

“…The delayed language development and frontotemporal pachygyria in brain MRI (Figure S2B) were compatible with the earlier findings of CRADD (MRT34; OMIM # 614499). The higher minor allele frequency (MAF, 0.0049) of the p.(Arg170His) variant in the Finnish population is consistent with previous reports of this variant as a founder allele in the Finnish population (Polla et al 2019 ).…”

“…In family FIN38 a Finnish founder variant [p.(Arg170His)] (Polla et al 2019 ) and a novel start loss variant [p.(Met1?)] in CRADD were identified.…”

The landscape of autosomal-recessive pathogenic variants in European populations reveals phenotype-specific effects

“…The results in both the Dutch and Estonian cohorts show that ~25% carries a PLP variant in an ID gene, almost all of these variants being rare. There is a single common allele (0.5%) in the Estonian cohort in the CRADD gene which is a well-known cause of AR syndromic ID, and likely represents a Northern Scandinavian (Finnish) founder mutation 19 . These observations are in line with previous studies on individuals with ID and other neurodevelopmental disorders (NDD) from outbred populations, which showed a very small (2-3%) contribution of AR variants to ID, with de novo pathogenic variants explaining the majority of patients 20,21,22 .…”

Biallelic mutations in the death domain of PIDD1 impair caspase-2 activation and are associated with intellectual disability

“…1 ). Mild lissencephaly has also been reported in affected individuals [2][3][4][5][6] , and megalencephaly without obvious cortical lamination defects in Cradd null mice 2 . Together with PIDD1 (p53-Induced Death Domain protein 1), CRADD can activate caspase-2-an endopeptidase thought to regulate apoptosis upon DNA damage in the so-called PIDDosome complex [see ref.…”