Abstract
BackgroundCerebellar atrophy and developmental delay are commonly associated features in large numbers of genetic diseases that frequently also include epilepsy. These defects are highly heterogeneous on both the genetic and clinical levels. Patients with these signs also typically present with non-specific neuroimaging results that can help prioritize further investigation but don’t suggest a specific molecular diagnosis.MethodsTo genetically explore a cohort of 18 Egyptian families with undiagnosed cerebellar atrophy identified on MRI, we sequenced probands and some non-affected family members via high-coverage whole exome sequencing (WES; >97 % of the exome covered at least by 30x). Patients were mostly from consanguineous families, either sporadic or multiplex. We analyzed WES data and filtered variants according to dominant and recessive inheritance models.ResultsWe successfully identified disease-causing mutations in half of the families screened (9/18). These mutations are located in seven different genes, PLA2G6 being the gene most frequently mutated (n = 3). We also identified a recurrent de novo mutation in the KIF1A gene and a molybdenum cofactor deficiency caused by the loss of the start codon in the MOCS2A open-reading frame in a mildly affected subject.ConclusionsThis study illustrates the necessity of screening for dominant mutations in WES data from consanguineous families. Our identification of a patient with a mild and improving phenotype carrying a previously characterized severe loss of function mutation also broadens the clinical spectrum associated with molybdenum cofactor deficiency.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-016-0436-9) contains supplementary material, which is available to authorized users.
Highlights
Cerebellar atrophy and developmental delay are commonly associated features in large numbers of genetic diseases that frequently include epilepsy
We identified pathological mutations in 7 genes within nine families (9/18; 50 %): a homozygous TPP1 mutation c.790C > T (NM_000391.3) p.Gln264* in family CIE7; a homozygous EXOSC3 mutation c.395A > C (NM_ 016042.3) p.Asp132Ala in CIE9; a homozygous PLA2G6 c.2070_2072del (NM_003560.2) p.Val691del mutation in families CIE11 and CIE13; a homozygous MOCS2 c.3G > A (NM_176806.3) p.Met1? mutation in CIE12; a homozygous SURF1 mutation c.237G > A (NM_003172.3) p.Trp79* in CIE16; a homozygous MFSD8 c.1213C > T (NM_152778.2) p.Gln405* mutation in family CIE17; a de novo KIF1A mutation c.173C > T (NM_001244008.1) p.Ser58Leu in family CIE21 and a homozygous PLA2G6 mutation c.1613G > A (NM_003560.2) p.Arg538His in family CIE29
Described mutations were identified in six genes TPP1, EXOSC3, PLA2G6, MOCS2 and SURF1 and KIF1A
Summary
Cerebellar atrophy and developmental delay are commonly associated features in large numbers of genetic diseases that frequently include epilepsy. These defects are highly heterogeneous on both the genetic and clinical levels. Atrophy and hypoplasia of the cerebellum are neuroradiological findings identified in pediatric-onset cerebellar ataxias and generally associated with imbalance, poor coordination and developmental delay. Hereditary cerebellar atrophy in childhood is a clinically and genetically heterogeneous group of conditions. They include a vast number of differential diagnoses with overlapping clinical findings such as intellectual disability and epilepsy [1, 2]. The loss of Purkinje cells could play a central role in the pathology of many cerebellar ataxias as they are highly metabolic cells and these cells are the only out-put of the cerebellum
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