Creatine transporter defect diagnosed by proton NMR spectroscopy in males with intellectual disability.

Creatine deficiency syndrome due to mutations in X-linked SLC6A8 gene results in nonspecific intellectual disability (ID). Diagnosis cannot be established on clinical grounds and is often based on the assessment of brain creatine levels by magnetic resonance spectroscopy (MRS). Considering high costs of MRS and necessity of sedation, this technique cannot be used as a first level-screening test. Likewise, gene test analysis is time consuming and not easily accessible to all laboratories. In this article feasibility of urine analysis (creatine/creatinine (Cr/Crn) ratio) performed by nuclear magnetic resonance (NMR) as a first level-screening test is explored. Before running a systematic selection of cases a preliminary study for further molecular analysis is shown. NMR urine spectra (n = 1,347) of male patients with an ID without a clinically recognizable syndrome were measured. On the basis of abnormal Cr/Crn ratio, three patients with the highest values were selected for molecular analysis. A confirmatory second urine test was positive in two patients and diagnosis was further confirmed by a decreased brain creatine level and by SLC6A8 gene analysis. A de novo mutation was identified in one. Another patient inherited a novel mutation from the mother who also has a mild ID. A repeat urine test was negative in the third patient and accordingly creatine level in the brain and SLC6A8 gene analysis both gave a normal result. We conclude that Cr/Crn ratio measured by NMR for male patients represents a rapid and useful first level screening test preceding molecular analysis

YWHAE loss of function causes a rare neurodevelopmental disease with brain abnormalities in human and mouse.

Miller-Dieker syndrome is caused by a multiple gene deletion, including PAFAH1B1 and YWHAE. Although deletion of PAFAH1B1 causes lissencephaly unambiguously, deletion of YWHAE alone has not clearly been linked to a human disorder. Cases with YWHAE variants were collected through international data sharing networks. To address the specific impact of YWHAE loss of function, we phenotyped a mouse knockout of Ywhae. We report a series of 10 individuals with heterozygous loss-of-function YWHAE variants (3 single-nucleotide variants and 7 deletions <1 Mb encompassing YWHAE but not PAFAH1B1), including 8 new cases and 2 follow-ups, added with 5 cases (copy number variants) from literature review. Although, until now, only 1 intragenic deletion has been described in YWHAE, we report 4 new variants specifically in YWHAE (3 splice variants and 1 intragenic deletion). The most frequent manifestations are developmental delay, delayed speech, seizures, and brain malformations, including corpus callosum hypoplasia, delayed myelination, and ventricular dilatation. Individuals with variants affecting YWHAE alone have milder features than those with larger deletions. Neuroanatomical studies in Ywhae <sup>-/-</sup> mice revealed brain structural defects, including thin cerebral cortex, corpus callosum dysgenesis, and hydrocephalus paralleling those seen in humans. This study further demonstrates that YWHAE loss-of-function variants cause a neurodevelopmental disease with brain abnormalities

Mutation spectrum of MLL2 in a cohort of kabuki syndrome patients

ABSTRACT: BACKGROUND: Kabuki syndrome (Niikawa-Kuroki syndrome) is a rare, multiple congenital anomalies/mental retardation syndrome characterized by a peculiar face, short stature, skeletal, visceral and dermatoglyphic abnormalities, cardiac anomalies, and immunological defects. Recently mutations in the histone methyl transferase MLL2 gene have been identified as its underlying cause. METHODS: Genomic DNAs were extracted from 62 index patients clinically diagnosed as affected by Kabuki syndrome. Sanger sequencing was performed to analyze the whole coding region of the MLL2 gene including intron-exon junctions. The putative causal and possible functional effect of each nucleotide variant identified was estimated by in silico prediction tools. RESULTS: We identified 45 patients with MLL2 nucleotide variants. 38 out of the 42 variants were never described before. Consistently with previous reports, the majority are nonsense or frameshift mutations predicted to generate a truncated polypeptide. We also identified 3 indel, 7 missense and 3 splice site. CONCLUSIONS: This study emphasizes the relevance of mutational screening of the MLL2 gene among patients diagnosed with Kabuki syndrome. The identification of a large spectrum of MLL2 mutations possibly offers the opportunity to improve the actual knowledge on the clinical basis of this multiple congenital anomalies/mental retardation syndrome, design functional studies to understand the molecular mechanisms underlying this disease, establish genotype-phenotype correlations and improve clinical management

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Extending the Use of Bioplastic Granules for the Application of Trichoderma Biocontrol Isolates in Flori/Horticulture and Turfgrass

Bioplastic materials are gaining increasing interest in a variety of different industrial and 13 domestic applications. Beside its usage as mulching films and plant clips in horticulture, no other 14 agricultural applications have been proposed. In 2009 we demonstrated that granules made of the 15 bioplastic Mater-Bi are an efficient and practical solution for field applications of biocontrol 16 isolates of the fungus Aspergillus flavus. Here, we investigated the feasibility to extend this 17 approach for delivering propagules of two biocontrol Trichoderma isolates with the final objective 18 to control damping-off of selected bedding, horticultural and turfgrass species. Bioplastic granules 19 entrapping conidia of Trichoderma virens Gv29-8 or T. harzianum ATCC 20847 were applied to a 20 potting mix infested with the fungal pathogen Rhizoctonia solani. Both isolates showed a positive 21 effect in reducing damping-off disease of impatiens and tomato seedlings. In the case of potting mix 22 infested with the lowest level of pathogen propagules causing 30% of damping-off, application of 23 1% (w/w) of inoculated granules resulted in 5 and 3% of impatiens and tomato seedlings, 24 respectively, affected by damping-off. With a more severe infestation (50% of damping-off), 25 amending the potting mixture with 10% bioplastic granules produced an average of 91% 26 suppression of damping-off in both species. Granules entrapping conidia of the biocontrol isolate 27 ATCC 20847 were significantly more effective in protecting impatiens and tomato seedlings. The 28 experiment was repeated with potting mix infested with Pythium ultimum and planted with annual 29 bluegrass. Bioplastic granules inoculated with the T. harzianum isolate significantly reduced (~ 30 90%) the impact of damping-off caused by this pathogen. Results from this study indicated that the 31 usage of this bioplastic-based formulation has the potential to be extended for the biocontrol of 32 damping-off in flori/horticulture crops and turfgrass

14q12 Microdeletion syndrome and congenital variant of Rett syndrome.

Contains fulltext : 81782.pdf (publisher's version ) (Closed access)Only two patients with 14q12 deletion have been reported to date. Here, we describe an additional patient with a similar deletion in order to improve the clinical delineation of this new microdeletion syndrome. The emerging phenotype is characterized by a Rett-like clinical course with an almost normal development during the first months of life followed by a period of regression. A peculiar facial phenotype is also present and it is characterized by mild dysmorphisms such as downslanting palpebral fissures, bilateral epicanthic folds, depressed nasal bridge, bulbous nasal tip, tented upper lip, everted lower lip and large ears. The relationship between this microdeletion syndrome and the congenital variant of Rett syndrome due to point mutations in one of the genes included in the deleted region, FOXG1, is discussed

CNS abnormalities in retinoblastoma patients

Purpose The presence of CNS abnormalities on MR images in a large group of consecutive patients with retinoblastoma (RTB) is evaluated. Mental retardation and congenital brain anomalies are reported in patients with RTB, mostly in combination with 13q deletion syndrome. Pineoblastoma (PNB) is the most important and “life threatening” condition associated with hereditary RTB, but recent studies suggest an association with pineal cysts. This association is important because some PNB mimic pineal cysts Methods CNS MR images of 320 consecutive patients with RTB from 2000 to 2010 were evaluated by neuroradiologists for tumors, structural anomalies, myelinization, and coincidental findings. Clinical records were reviewed for laterality, heredity, and the presence of the 13q deletion syndrome. Results The hereditary group (patients with bilateral and unilateral proved RB1-germline mutation) included 42 (48.2%) of 87 patients. Nine patients had 13q deletion syndrome. Normal findings on brain MR images were seen in 305 (95.3%) patients. One PNB was detected in a patient with hereditary RTB and 2 arachnoid cysts in 2 sporadic unilateral RTB patients; one cerebral and corpus callosum atrophy and 3 pineal cysts were also detected (2 non hereditary, 1 in 13q deletion syndrome). Corpus callosum agenesis was found in 3 patients (two in 13q deletion syndrome, 1 in hereditary RTB) and corpus callosum hypoplasia in 6 patients (2 twins, 4 sporadic RTB, 1 familial RTB). Chiari I syndrome was found in two cases Conclusion PNB is associated with hereditary RTB, and structural brain abnormalities are associated not only with 13q deletion syndrome. Pineal cysts can be detected in patients with sporadic RTB and/or with 13q deletion syndrome

Early-onset seizure variant of Rett syndrome: Definition of the clinical diagnostic criteria.

BACKGROUND: Rett syndrome is a severe neurodevelopmental disorder affecting almost exclusively females. Among Rett clinical variants, the early-onset seizure variant describes girls with early onset epilepsy and it is caused by mutations in CDKL5. METHODS: Four previously reported girls and five new cases with CDKL5 mutation, ranging from 14 months to 13 years, were evaluated by two clinical geneticists, classified using a severity score system based on the evaluation of 22 different clinical signs and compared with 128 classic Rett and 25 Zappella variant MECP2-mutated patients, evaluated by the same clinical geneticists. Clinical features were compared with previously described CDKL5 mutated patients. Both the statistical and the descriptive approach have been used to delineate clinical diagnostic criteria. RESULTS: All girls present epilepsy with onset varying from 10 days to 3 months. Patients may present different type of seizures both at onset and during the whole course of the disease; multiple seizure types may also occur in the same individual. After treatment with antiepileptic drugs patients may experience a short seizure-free period but epilepsy progressively relapses. Typical stereotypic hand movements severely affecting the ability to grasp are present. Psychomotor development is severely impaired. In the majority of cases head circumference is within the normal range both at birth and at the time of clinical examination. CONCLUSION: For the practical clinical approach we propose to use six necessary and eight supportive diagnostic criteria. Epilepsy with onset between the first week and 5 months of life, hand stereotypies, as well as severe hypotonia, are included among the necessary criteria