Autozygosity-driven genetic diagnosis in consanguineous families from Italy and the Greater Middle East

Abstract

Autozygosity-driven exome analysis has been shown effective for identification of genes underlying recessive diseases especially in countries of the so-called Greater Middle East (GME), where high consanguinity unravels the phenotypic effects of recessive alleles and large family sizes facilitate homozygosity mapping. In Italy, as in most European countries, consanguinity is estimated low.Nonetheless, consanguineous Italian families are not uncommon in publications of genetic findings and are often key to new associations of genes with rare diseases. We collected 52 patients from 47 consanguineous families with suspected recessive diseases, 29 originated in GME countries and 18 of Italian descent. We performed autozygosity-driven exome analysis by detecting long runs of homozygosity (ROHs>1.5 Mb) and by prioritizing candidate clinical variants within. We identified a pathogenic synonymous variant that had been previously missed in NARS2 and we increased an initial high diagnostic rate (47%) to 55% by matchmaking our candidate genes and including in the analysis shorter ROHs that may also happen to be autozygous. GME and Italian families contributed to diagnostic yield comparably. We found no significant difference either in the extension of the autozygous genome, or in the distribution of candidate clinical variants between GME and Italian families, while we showed that the average autozygous genome was larger and the mean number of candidate clinical variants was significantly higher (p=0.003) in mutation-positive than in mutationnegative individuals, suggesting that these features influence the likelihood that the disease is autozygosity-related. We highlight the utility of autozygosity-driven genomic analysis also in countries and/or communities where consanguinity is not widespread cultural tradition.Patients. This study includes 47 families referred in years 2012-2017 to the Medical Genetics Unit,

Expanding phenotype heterogeneity of NARS2 by presenting subdural hematoma and parenchymal hemorrhage

“…T2-weighted hyperintensity in different parts of the brain, cerebral atrophy, restricted diffusion in the temporal lobe, left basal ganglia and cerebral cortex, diffuse atrophy, deep gray matter, subdural effusions, asymmetry of the hippocampus were the most brain disorders observed in available MRI results. 6,7,9,10,[13][14][15]19 Bilateral synchronous spike and polyspike waves mainly in the posterior part of the brain, focal discharges, multifocal and spikes and sharp waves in addition to slow waves and irregular spikes in the central, parietal, and temporal regions were some of abnormal EEG results shown in some patients. 7,16,19,20 Muscle biopsy in some patients revealed slightly increased lipid/ atrophic fibers, atrophic fibers, ragged red fibers, enlarged mitochondria, increased lipid profile, mitochondrial subsarcolemmal proliferation, diffuse presence of COX-negative fibers and lipid droplets, decreased complexes II and subtle atrophy of the muscle fibers.…”

“…6,7,9,10,[13][14][15]19 Bilateral synchronous spike and polyspike waves mainly in the posterior part of the brain, focal discharges, multifocal and spikes and sharp waves in addition to slow waves and irregular spikes in the central, parietal, and temporal regions were some of abnormal EEG results shown in some patients. 7,16,19,20 Muscle biopsy in some patients revealed slightly increased lipid/ atrophic fibers, atrophic fibers, ragged red fibers, enlarged mitochondria, increased lipid profile, mitochondrial subsarcolemmal proliferation, diffuse presence of COX-negative fibers and lipid droplets, decreased complexes II and subtle atrophy of the muscle fibers. 6,7,10,11,19 Among all patients reviewed in this article, 8 patients died at the ages of 5.5, 6, 9, 14 and 15 months and 6, 16 years old.…”

“…Increased blood lactate level was the most prevalent anomaly in laboratory results. 6,9,10,13,15,19 Although MRI results were not available for all patients, abnormal results were observed in some individuals. T2-weighted hyperintensity in different parts of the brain, cerebral atrophy, restricted diffusion in the temporal lobe, left basal ganglia and cerebral cortex, diffuse atrophy, deep gray matter, subdural effusions, asymmetry of the hippocampus were the most brain disorders observed in available MRI results.…”

“…7,16,19,20 Muscle biopsy in some patients revealed slightly increased lipid/ atrophic fibers, atrophic fibers, ragged red fibers, enlarged mitochondria, increased lipid profile, mitochondrial subsarcolemmal proliferation, diffuse presence of COX-negative fibers and lipid droplets, decreased complexes II and subtle atrophy of the muscle fibers. 6,7,10,11,19 Among all patients reviewed in this article, 8 patients died at the ages of 5.5, 6, 9, 14 and 15 months and 6, 16 years old. 6,7,10,13,15,20 Other patients were alive at the time of the review at the ages of 2 and 28 months and 1, 2, 8, 17, 22, 25, 26, 29 and 34 years old.…”

De novo and bi-allelic variants in AP1G1 cause neurodevelopmental disorder with developmental delay, intellectual disability, and epilepsy

“…24 Collectively, we investigated eleven families with variants in AP1G1 (GenBank: NM_001030007.2; Figure 1). Two bi-allelic homozygous missense variants (c.737C>A [p.Pro246His] and c.1105A>G [p.Met369Val]) were found in available affected individuals from two distinct families with Italian 25 (CPBO) and Pakistani (PKMR328) origins, respectively. Moreover, eight de novo heterozygous variants were identified in nine isolated affected individuals from nine families (Figure 1C 1D).…”