Integrated exome and transcriptome analysis prioritizes MAP4K4 de novo frameshift variants in autism spectrum disorder as a novel disease-gene association.

The application of next-generation sequencing (NGS) to clinical practice is still hampered by the ability to interpret the clinical relevance of novel variants and the difficulty of evaluating their effect in specific tissues. Here, we applied integrated genomic approaches for interrogating blood samples of two unrelated individuals with neurodevelopmental disorders and identified a novel neuro-pathogenic role for the Mitogen-Activated Protein Kinase 4 gene (MAP4K4). In particular, we identified two novel frameshift variants in coding exons expressed in the blood and neuronal isoforms. Both variants were predicted to generate non-sense-mediated decay. By transcriptome analysis, we simultaneously demonstrated the deleterious effect of the identified variants on the splicing activity and stability of MAP4K4 mRNA. Therefore, we propose MAP4K4 as a novel causative gene for non-syndromic and syndromic neurodevelopmental disorders. Altogether, we prove the efficacy of an integrated approach of exome and transcriptome sequencing in the resolution of undiagnosed cases by leveraging the analysis of variants in genes expressed in peripheral blood.

Genetics of lipedema: new perspectives on genetic research and molecular diagnoses.

OBJECTIVE: The aim of this qualitative review is to provide an update on the current understanding of the genetic determinants of lipedema and to develop a genetic test to differentiate lipedema from other diagnoses. MATERIALS AND METHODS: An electronic search was conducted in MEDLINE, PubMed, and Scopus for articles published in English up to March 2019. Lipedema and similar disorders included in the differential diagnosis of lipedema were searched in the clinical synopsis section of OMIM, in GeneCards, Orphanet, and MalaCards. RESULTS: The search identified several genetic factors related to the onset of lipedema and highlighted the utility of developing genetic diagnostic testing to help differentiate lipedema from other diagnoses. CONCLUSIONS: No genetic tests or guidelines for molecular diagnosis of lipedema are currently available, despite the fact that genetic testing is fundamental for the differential diagnosis of lipedema against Mendelian genetic obesity, primary lymphedema, and lipodystrophies.

Say-Barber-Biesecker-Young-Simpson syndrome and Genitopatellar syndrome: Lumping or splitting?

The Say-Barber-Biesecker-Young-Simpson variant of Ohdo syndrome (SBBYSS) and Genitopatellar syndrome (GTPTS) are 2 rare but clinically well-described diseases caused by de novo heterozygous sequence variants in the KAT6B gene. Both phenotypes are characterized by significant global developmental delay/intellectual disability, hypotonia, genital abnormalities, and patellar hypoplasia/agenesis. In addition, congenital heart defects, dental abnormalities, hearing loss, and thyroid anomalies are common to both phenotypes. This broad clinical overlap led some authors to propose the concept of KAT6B spectrum disorders. On the other hand, some clinical features could help to differentiate the 2 disorders. Furthermore, it is possible to establish a genotype-phenotype correlation when considering the position of the sequence variant along the gene, supporting the notion of the 2 disorders as really distinct entities.

SNORD116 deletions cause Prader-Willi syndrome with a mild phenotype and macrocephaly.

Prader-Willi syndrome is a complex condition caused by lack of expression of imprinted genes in the paternally derived region of chromosome 15 (15q11q13). A small number of patients with Prader-Willi phenotype have been discovered to have narrow deletions, not encompassing the whole critical region, but only the SNORD116 cluster, which includes genes codifying for small nucleolar RNAs. This kind of deletion usually is not detected by the classic DNA methylation analysis test. We present the case of a male patient with a mild Prader-Willi phenotype and a small deletion including SNORD116, diagnosed by methylation-sensitive multiplex ligation-dependent probe amplification (MLPA. The patient showed neonatal hypotonia, hyperphagia, obesity, central hypogonadism, hypothyroidism, strabismus. Stature and intellectual development are within the normal range. The presence of macrocephaly, observed in other cases of SNORD116 deletions as well, is uncommon for the classic phenotype of the syndrome.

DNA methylation in intron 1 of the frataxin gene is related to GAA repeat length and age of onset in Friedreich ataxia patients.

BACKGROUND: The most frequent mutation of Friedreich ataxia (FRDA) is the abnormal expansion of a GAA repeat located within the first intron of FXN gene. It is known that the length of GAA is directly correlated with disease severity. The effect of mutation is a severe reduction of mRNA. Recently, a link among aberrant CpG methylation, chromatin organisation and GAA repeat was proposed. METHODS: In this study, using pyrosequencing technology, we have performed a quantitative analysis of the methylation status of five CpG sites located within the region upstream of GAA repeat, in 67 FRDA patients. RESULTS: We confirm previous observation about differences in the methylation degree between FRDA individuals and controls. We showed a direct correlation between CpG methylation and triplet expansion size. Significant differences were found for each CpG tested (ANOVA p<0.001). These differences were largest for CpG1 and CpG2: 84.45% and 76.80%, respectively, in FRDA patients compared to 19.65% and 23.34% in the controls. Most importantly, we found a strong inverse correlation between CpG2 methylation degree and age of onset (Spearman's rho = -0.550, p<0.001). CONCLUSION: Because epigenetic changes may cause or contribute to gene silencing, our data may have relevance for the therapeutic approach to FRDA. Since the analysis can be performed in peripheral blood leucocytes (PBL), evaluation of the methylation status of specific CpG sites in FRDA patients could be a convenient biomarker.

[Neurofibroma of the recurrent nerve: apropos of a case]. / Neurofibrome du nerf recurrent: à propos d'un cas.

A case of solitary benign neurofibroma of the recurrent laryngeal nerve is presented. The preoperative diagnosis was in favour of a thyroid cancer. The discovery of this benign tumour leads to discuss the malignancy criteria of a cold nodule. The recurrential paralysis is an evidence of malignancy in only about 80% of cases. The surgical operation is the best treatment because it allows the histology that asserts the benignancy of the lesion. The review of the literature confirms the exceptional nature of this tumour. The respective histology of neurofibromas is finally briefly recalled.

Effect of regular and decaffeinated coffee on serum gastrin levels.

We evaluated the hypothesis that the noncaffeine gastric acid stimulant effect of coffee might be by way of serum gastrin release. After 10 healthy volunteers drank 50 ml of coffee solution corresponding to one cup of home-made regular coffee containing 10 g of sugar and 240 mg/100 ml of caffeine, serum total gastrin levels peaked at 10 min and returned to basal values within 30 min; the response was of little significance (1.24 times the median basal value). Drinking 100 ml of sugared water (as control) resulted in occasional random elevations of serum gastrin which were not statistically significant. Drinking 100 ml of regular or decaffeinated coffee resulted in a prompt and lasting elevation of total gastrin; mean integrated outputs after regular or decaffeinated coffee were, respectively, 2.3 and 1.7 times the values in the control test. Regular and decaffeinated coffees share a strong gastrin-releasing property. Neither distension, osmolarity, calcium, nor amino acid content of the coffee solution can account for this property, which should be ascribed to some other unidentified ingredient. This property is at least partially lost during the process of caffeine removal.

[The problem of aeration of the ear during closed techniques (author's transl)]. / Le problème de l'aération de l'oreille au cours des techniques fermées.

One of the major problem in otology today is maintaining aerated middle space when there is malfunction of the eustachian tube. The "closed technical" preserved the anatomy of the external and middle ears, but unknown the persistent non function of the eustachian tube. Also, in cholesteatoma a permanent aerating tube is utilised at the time of the initial surgery. The tube is placed through hale drilled in the attical boy canal wall, over the head of the malleus. The "trans attical tube" is found to be a valuable adjuction in intact canal wall tympanoplasty for hearing improvement and to reduce the incidence of a retraction pocket.

AOTA human resources project. 4. The member data survey--demographic characteristics of occupational therapy personnel.

This article is the fourth in a series describing the American Occupational Therapy Association's Human Resources Project. The Project consists of several interrelated studies aimed at identifying the supply of occupational therapists and assistants in the United States as of December 1973, and at projecting requirements for their services. The present report is the second of several that will describe the results of the Member Data Survey, the objective of which is to define the geographic, demographic, educational, and employment characteristics of the AOTA membership.

AOTA Human Resources Project: 3. The member data survey.

This article is the third in a series describing the American Occupational Therapy Association's Human Resources Project. The Project consists of several interrelated studies aimed at identifying the supply of occupational therapists and assistants in the United States as of December 1973, and at projecting requirements for their services. The present report is the first of several that will describe the results of the Member Data Survey, the objective of which is to define the geographic, demographic, educational, and employment characteristics of the AOTA membership.

AOTA Human Resources Project. The education study.

This article is the second in a series describing the American Occupational Therapy Association's Human Resources Project. The project, comprised of several interrelated studies, is aimed at identifying the supply of occupational therapists and assistants in the United States as of December 1973, and at describing the projected requirements for their services. The present report describes the initial phase of the Education Study, the objective of which is to define the total supply of occupational therapy manpower, regardless of membership status in the AOTA.