SNP array and FISH analysis of a proband with a 22q13.2- 22qter duplication shed light on the molecular origin of the rearrangement

Background In about one third of healthy subjects, the microscopic analysis of chromosomes reveals heteromorphisms with no clinical implications: for example changes in size of the short arm of acrocentric chromosomes. In patients with a pathological phenotype, however, a large acrocentric short arm can mask a genomic imbalance and should be investigated in more detail. We report the first case of a chromosome 22 with a large acrocentric short arm masking a partial trisomy of the distal long arm, characterized by SNP array. We suggest a possible molecular mechanism underlying the rearrangement. Case presentation We report the case of a 15-year-old dysmorphic girl with low grade psychomotor retardation characterized by a karyotype with a large acrocentric short arm of one chromosome 22. Cytogenetic analysis revealed a normal karyotype with a very intense Q-fluorescent and large satellite on the chromosome 22 short arm. Fluorescence in situ hybridisation analysis showed a de novo partial trisomy of the 22q13.2-qter chromosome region attached to the short arm of chromosome 22. SNP-array analysis showed that the duplication was 8.5 Mb long and originated from the paternal chromosome. Haplotype analysis revealed that the two paternal copies of the distal part of chromosome 22 have the same haplotype and, therefore, both originated from the same paternal chromosome 22. A possible molecular mechanism that could explain this scenario is a break-induced replication (BIR) which is involved in non-reciprocal translocation events. Conclusion The combined use of FISH and SNP arrays was crucial for a better understanding of the molecular mechanism underlying this rearrangement. This strategy could be applied for a better understanding of the molecular mechanisms underlying cryptic chromosomal rearrangements

Exome sequencing in schizophrenic patients with high levels of homozygosity identifies novel and extremely rare mutations in the GABA/glutamatergic pathways

Inbreeding is a known risk factor for recessive Mendelian diseases and previous studies have suggested that it could also play a role in complex disorders, such as psychiatric diseases. Recent inbreeding results in the presence of long runs of homozygosity (ROHs) along the genome, which are also defined as autozygosity regions. Genetic variants in these regions have two alleles that are identical by descent, thus increasing the odds of bearing rare recessive deleterious mutations due to a homozygous state. A recent study showed a suggestive enrichment of long ROHs in schizophrenic patients, suggesting that recent inbreeding could play a role in the disease. To better understand the impact of autozygosity on schizophrenia risk, we selected, from a cohort of 180 Italian patients, seven subjects with extremely high numbers of large ROHs that were likely due to recent inbreeding and characterized the mutational landscape within their ROHs using Whole Exome Sequencing and, gene set enrichment analysis. We identified a significant overlap (17%; empirical p-value = 0.0171) between genes inside ROHs affected by low frequency functional homozygous variants (107 genes) and the group of most promising candidate genes mutated in schizophrenia. Moreover, in four patients, we identified novel and extremely rare damaging mutations in the genes involved in neurodevelopment (MEGF8) and in GABA/glutamatergic synaptic transmission (GAD1, FMN1, ANO2). These results provide insights into the contribution of rare recessive mutations and inbreeding as risk factors for schizophrenia. ROHs that are likely due to recent inbreeding harbor a combination of predisposing low-frequency variants and extremely rare variants that have a high impact on pivotal biological pathways implicated in the disease. In addition, this study confirms that focusing on patients with high levels of homozygosity could be a useful prioritization strategy for discovering new high-impact mutations in genetically complex disorders

Mutations impairing GSK3-mediated MAF phosphorylation cause cataract, deafness, intellectual disability, seizures, and a down syndrome-like facies

Transcription factors operate in developmental processes to mediate inductive events and cell competence, and perturbation of their function or regulation can dramatically affect morphogenesis, organogenesis, and growth. We report that a narrow spectrum of amino-acid substitutions within the transactivation domain of the v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog (MAF), a leucine zipper-containing transcription factor of the AP1 superfamily, profoundly affect development. Seven different de novo missense mutations involving conserved residues of the four GSK3 phosphorylation motifs were identified in eight unrelated individuals. The distinctive clinical phenotype, for which we propose the eponym Aymé-Gripp syndrome, is not limited to lens and eye defects as previously reported for MAF/Maf loss of function but includes sensorineural deafness, intellectual disability, seizures, brachycephaly, distinctive flat facial appearance, skeletal anomalies, mammary gland hypoplasia, and reduced growth. Disease-causing mutations were demonstrated to impair proper MAF phosphorylation, ubiquitination and proteasomal degradation, perturbed gene expression in primary skin fibroblasts, and induced neurodevelopmental defects in an in vivo model. Our findings nosologically and clinically delineate a previously poorly understood recognizable multisystem disorder, provide evidence for MAF governing a wider range of developmental programs than previously appreciated, and describe a novel instance of protein dosage effect severely perturbing developmen

New Copy Number Variations in Schizophrenia

Genome-wide screenings for copy number variations (CNVs) in patients with schizophrenia have demonstrated the presence of several CNVs that increase the risk of developing the disease and a growing number of large rare CNVs; the contribution of these rare CNVs to schizophrenia remains unknown. Using Affymetrix 6.0 arrays, we undertook a systematic search for CNVs in 172 patients with schizophrenia and 160 healthy controls, all of Italian origin, with the aim of confirming previously identified loci and identifying novel schizophrenia susceptibility genes. We found five patients with a CNV occurring in one of the regions most convincingly implicated as risk factors for schizophrenia: NRXN1 and the 16p13.1 regions were found to be deleted in single patients and 15q11.2 in 2 patients, whereas the 15q13.3 region was duplicated in one patient. Furthermore, we found three distinct patients with CNVs in 2q12.2, 3q29 and 17p12 loci, respectively. These loci were previously reported to be deleted or duplicated in patients with schizophrenia but were never formally associated with the disease. We found 5 large CNVs (>900 kb) in 4q32, 5q14.3, 8q23.3, 11q25 and 17q12 in five different patients that could include some new candidate schizophrenia susceptibility genes. In conclusion, the identification of previously reported CNVs and of new, rare, large CNVs further supports a model of schizophrenia that includes the effect of multiple, rare, highly penetrant variants

Sometimes Sperm Whales (Physeter macrocephalus) Cannot Find Their Way Back to the High Seas: A Multidisciplinary Study on a Mass Stranding

BACKGROUND: Mass strandings of sperm whales (Physeter macrocephalus) remain peculiar and rather unexplained events, which rarely occur in the Mediterranean Sea. Solar cycles and related changes in the geomagnetic field, variations in water temperature and weather conditions, coast geographical features and human activities have been proposed as possible causes. In December 2009, a pod of seven male sperm whales stranded along the Adriatic coast of Southern Italy. This is the sixth instance from 1555 in this basin. METHODOLOGY/PRINCIPAL FINDINGS: Complete necropsies were performed on three whales whose bodies were in good condition, carrying out on sampled tissues histopathology, virology, bacteriology, parasitology, and screening of veins looking for gas emboli. Furthermore, samples for age determination, genetic studies, gastric content evaluation, stable isotopes and toxicology were taken from all the seven specimens. The animals were part of the same group and determined by genetic and photo-identification to be part of the Mediterranean population. Causes of death did not include biological agents, or the "gas and fat embolic syndrome", associated with direct sonar exposure. Environmental pollutant tissue concentrations were relatively high, in particular organochlorinated xenobiotics. Gastric content and morphologic tissue examinations showed a prolonged starvation, which likely caused, at its turn, the mobilization of lipophilic contaminants from the adipose tissue. Chemical compounds subsequently entered the blood circulation and may have impaired immune and nervous functions. CONCLUSIONS/SIGNIFICANCE: A multi-factorial cause underlying this sperm whales' mass stranding is proposed herein based upon the results of postmortem investigations as well as of the detailed analyses of the geographical and historical background. The seven sperm whales took the same "wrong way" into the Adriatic Sea, a potentially dangerous trap for Mediterranean sperm whales. Seismic surveys should be also regarded as potential co-factors, even if no evidence of direct impact has been detected

Prescription appropriateness of anti-diabetes drugs in elderly patients hospitalized in a clinical setting: evidence from the REPOSI Register

Diabetes is an increasing global health burden with the highest prevalence (24.0%) observed in elderly people. Older diabetic adults have a greater risk of hospitalization and several geriatric syndromes than older nondiabetic adults. For these conditions, special care is required in prescribing therapies including anti- diabetes drugs. Aim of this study was to evaluate the appropriateness and the adherence to safety recommendations in the prescriptions of glucose-lowering drugs in hospitalized elderly patients with diabetes. Data for this cross-sectional study were obtained from the REgistro POliterapie-Società Italiana Medicina Interna (REPOSI) that collected clinical information on patients aged ≥ 65 years acutely admitted to Italian internal medicine and geriatric non-intensive care units (ICU) from 2010 up to 2019. Prescription appropriateness was assessed according to the 2019 AGS Beers Criteria and anti-diabetes drug data sheets.Among 5349 patients, 1624 (30.3%) had diagnosis of type 2 diabetes. At admission, 37.7% of diabetic patients received treatment with metformin, 37.3% insulin therapy, 16.4% sulfonylureas, and 11.4% glinides. Surprisingly, only 3.1% of diabetic patients were treated with new classes of anti- diabetes drugs. According to prescription criteria, at admission 15.4% of patients treated with metformin and 2.6% with sulfonylureas received inappropriately these treatments. At discharge, the inappropriateness of metformin therapy decreased (10.2%, P < 0.0001). According to Beers criteria, the inappropriate prescriptions of sulfonylureas raised to 29% both at admission and at discharge. This study shows a poor adherence to current guidelines on diabetes management in hospitalized elderly people with a high prevalence of inappropriate use of sulfonylureas according to the Beers criteria

Antidiabetic Drug Prescription Pattern in Hospitalized Older Patients with Diabetes

Objective: To describe the prescription pattern of antidiabetic and cardiovascular drugs in a cohort of hospitalized older patients with diabetes. Methods: Patients with diabetes aged 65 years or older hospitalized in internal medicine and/or geriatric wards throughout Italy and enrolled in the REPOSI (REgistro POliterapuie SIMI—Società Italiana di Medicina Interna) registry from 2010 to 2019 and discharged alive were included. Results: Among 1703 patients with diabetes, 1433 (84.2%) were on treatment with at least one antidiabetic drug at hospital admission, mainly prescribed as monotherapy with insulin (28.3%) or metformin (19.2%). The proportion of treated patients decreased at discharge (N = 1309, 76.9%), with a significant reduction over time. Among those prescribed, the proportion of those with insulin alone increased over time (p = 0.0066), while the proportion of those prescribed sulfonylureas decreased (p < 0.0001). Among patients receiving antidiabetic therapy at discharge, 1063 (81.2%) were also prescribed cardiovascular drugs, mainly with an antihypertensive drug alone or in combination (N = 777, 73.1%). Conclusion: The management of older patients with diabetes in a hospital setting is often sub-optimal, as shown by the increasing trend in insulin at discharge, even if an overall improvement has been highlighted by the prevalent decrease in sulfonylureas prescription