Multisystem inflammatory syndrome in children (MIS-C) is a rare condition following SARS-CoV-2 infection associated with intestinal manifestations. Genetic predisposition, including inborn errors of the OAS-RNAseL pathway, has been reported. We sequenced 154 MIS-C patients and utilized a novel statistical framework of gene burden analysis, "burdenMC," which identified an enrichment for rare predicted-deleterious variants in BTNL8 (OR = 4.2, 95% CI: 3.5-5.3, P < 10-6). BTNL8 encodes an intestinal epithelial regulator of Vγ4+γδ T cells implicated in regulating gut homeostasis. Enrichment was exclusive to MIS-C, being absent in patients with COVID-19 or bacterial disease. Using an available functional test for BTNL8, rare variants from a larger cohort of MIS-C patients (n = 835) were tested which identified eight variants in 18 patients (2.2%) with impaired engagement of Vγ4+γδ T cells. Most of these variants were in the B30.2 domain of BTNL8 implicated in sensing epithelial cell status. These findings were associated with altered intestinal permeability, suggesting a possible link between disrupted gut homeostasis and MIS-C-associated enteropathy triggered by SARS-CoV-2.
- MeSH
- butyrofiliny * genetika metabolismus MeSH
- COVID-19 * genetika komplikace imunologie virologie MeSH
- dítě MeSH
- genetická predispozice k nemoci MeSH
- heterozygot MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- předškolní dítě MeSH
- SARS-CoV-2 * MeSH
- syndrom systémové zánětlivé reakce * genetika MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- dějiny 20. století * MeSH
- dítě MeSH
- lidé MeSH
- pediatrie * dějiny MeSH
- Check Tag
- dějiny 20. století * MeSH
- dítě MeSH
- lidé MeSH
- Publikační typ
- historické články MeSH
- O autorovi
- Houštěk, Josef, 1913-1994 Autorita
• For children with growth hormone deficiency, once-weekly somatrogon injections were less of a burden than once-daily somatropin injections. • The safety of weekly somatrogon was similar to that of daily somatropin. • Compared with daily somatropin injections, children with growth hormone deficiency may be less likely to miss weekly somatrogon injections. ○ This is because weekly somatrogon injections were less of a burden and were less likely to interfere with daily activities compared with daily somatropin injections. The purpose of this plain language summary is to help you to understand the findings from recent research. • Somatrogon is used to treat the condition under study that is discussed in this summary. Approval varies by country; please check with your local provider for more details. • The results of this study may differ from those of other studies. Health professionals should make treatment decisions based on all available evidence and not on the results of a single study. This original scientific article on which this summary is based was published in the Journal of the Endocrine Society and can be accessed for free at: https://academic.oup.com/jes/article/6/10/bvac117/6695276. The details of the original article are as follows:Aristides K. Maniatis, Mauri Carakushansky, Sonya Galcheva, Gnanagurudasan Prakasam, Larry A. Fox, Adriana Dankovcikova, Jane Loftus, Andrew A. Palladino, Maria de los Angeles Resa, Carrie Turich Taylor, Mehul T. Dattani, Jan Lebl. Treatment burden of weekly somatrogon versus daily somatropin in children with growth hormone deficiency: a randomized study. J Endocr Soc 2022; 6(10): bvac117. DOI: 10.1210/jendso/bvac117.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
AIMS/HYPOTHESIS: Monogenic diabetes is estimated to account for 1-6% of paediatric diabetes cases in primarily non-consanguineous populations, while the incidence and genetic spectrum in consanguineous regions are insufficiently defined. In this single-centre study we aimed to evaluate diabetes subtypes, obtain the consanguinity rate and study the genetic background of individuals with syndromic and neonatal diabetes in a population with a high rate of consanguinity. METHODS: Data collection was carried out cross-sectionally in November 2021 at the paediatric diabetic clinic, Dr Jamal Ahmad Rashed Hospital, in Sulaimani, Kurdistan, Iraq. At the time of data collection, 754 individuals with diabetes (381 boys) aged up to 16 years were registered. Relevant participant data was obtained from patient files. Consanguinity status was known in 735 (97.5%) participants. Furthermore, 12 families of children with neonatal diabetes and seven families of children with syndromic diabetes consented to genetic testing by next-generation sequencing. Prioritised variants were evaluated using the American College of Medical Genetics and Genomics guidelines and confirmed by Sanger sequencing. RESULTS: A total of 269 of 735 participants (36.5%) with known consanguinity status were offspring of consanguineous families. An overwhelming majority of participants (714/754, 94.7%) had clinically defined type 1 diabetes (35% of them were born to consanguineous parents), whereas only eight (1.1%) had type 2 diabetes (38% consanguineous). Fourteen (1.9%) had neonatal diabetes (50% consanguineous), seven (0.9%) had syndromic diabetes (100% consanguineous) and 11 (1.5%) had clinically defined MODY (18% consanguineous). We found that consanguinity was significantly associated with syndromic diabetes (p=0.0023) but not with any other diabetes subtype. The genetic cause was elucidated in ten of 12 participants with neonatal diabetes who consented to genetic testing (homozygous variants in GLIS3 [sibling pair], PTF1A and ZNF808 and heterozygous variants in ABCC8 and INS) and four of seven participants with syndromic diabetes (homozygous variants in INSR, SLC29A3 and WFS1 [sibling pair]). In addition, a participant referred as syndromic diabetes was diagnosed with mucolipidosis gamma and probably has type 2 diabetes. CONCLUSIONS/INTERPRETATION: This unique single-centre study confirms that, even in a highly consanguineous population, clinically defined type 1 diabetes is the prevailing paediatric diabetes subtype. Furthermore, a pathogenic cause of monogenic diabetes was identified in 83% of tested participants with neonatal diabetes and 57% of participants with syndromic diabetes, with most variants being homozygous. Causative genes in our consanguineous participants were markedly different from genes reported from non-consanguineous populations and also from those reported in other consanguineous populations. To correctly diagnose syndromic diabetes in consanguineous populations, it may be necessary to re-evaluate diagnostic criteria and include additional phenotypic features such as short stature and hepatosplenomegaly.
- MeSH
- diabetes mellitus 1. typu * epidemiologie genetika MeSH
- diabetes mellitus 2. typu * epidemiologie genetika diagnóza MeSH
- dítě MeSH
- kohortové studie MeSH
- lidé MeSH
- mutace genetika MeSH
- nemoci novorozenců * genetika MeSH
- novorozenec MeSH
- pokrevní příbuzenství MeSH
- proteiny přenášející nukleosidy genetika MeSH
- senioři MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Irák MeSH
CONTEXT: Familial tall stature (FTS) is considered to be a benign variant of growth with a presumed polygenic etiology. However, monogenic disorders with possible associated pathological features could also be hidden under the FTS phenotype. OBJECTIVE: To elucidate the genetic etiology in families with FTS and to describe their phenotype in detail. METHODS: Children with FTS (the life-maximum height in both the child and his/her taller parent > 2 SD for age and sex) referred to the Endocrinology center of Motol University Hospital were enrolled into the study. Their DNA was examined cytogenetically and via a next-generation sequencing panel of 786 genes associated with growth. The genetic results were evaluated by the American College of Molecular Genetics and Genomics guidelines. All of the participants underwent standard endocrinological examination followed by specialized anthropometric evaluation. RESULTS: In total, 34 children (19 girls) with FTS were enrolled in the study. Their median height and their taller parent's height were 3.1 SD and 2.5 SD, respectively. The genetic cause of FTS was elucidated in 11/34 (32.4%) children (47,XXX and 47,XYY karyotypes, SHOX duplication, and causative variants in NSD1 [in 2], SUZ12 [in 2], FGFR3, CHD8, GPC3, and PPP2R5D genes). Ten children had absent syndromic signs and 24 had dysmorphic features. CONCLUSION: Monogenic (and cytogenetic) etiology of FTS can be found among children with FTS. Genetic examination should be considered in all children with FTS regardless of the presence of dysmorphic features.
- MeSH
- dítě MeSH
- fenotyp MeSH
- genetické testování * metody MeSH
- lidé MeSH
- mladiství MeSH
- poruchy růstu genetika diagnóza MeSH
- předškolní dítě MeSH
- tělesná výška * genetika MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Publikační typ
- abstrakt z konference MeSH
Because the causes of combined pituitary hormone deficiency (CPHD) are complex, the etiology of congenital CPHD remains unknown in most cases. The aim of the study was to identify the genetic etiology of CPHD in a well-defined single-center cohort. In total, 34 children (12 girls) with congenital CPHD (growth hormone (GH) deficiency and impaired secretion of at least one other pituitary hormone) treated with GH in our center were enrolled in the study. Their median age was 11.2 years, pre-treatment height was -3.2 s.d., and maximal stimulated GH was 1.4 ug/L. Of them, 30 had central adrenal insufficiency, 27 had central hypothyroidism, ten had hypogonadotropic hypogonadism, and three had central diabetes insipidus. Twenty-six children had a midline defect on MRI. Children with clinical suspicion of a specific genetic disorder underwent genetic examination of the gene(s) of interest via Sanger sequencing or array comparative genomic hybridization. Children without a detected causal variant after the first-tier testing or with no suspicion of a specific genetic disorder were subsequently examined using next-generation sequencing growth panel. Variants were evaluated by the American College of Medical Genetics standards. Genetic etiology was confirmed in 7/34 (21%) children. Chromosomal aberrations were found in one child (14q microdeletion involving the OTX2 gene). The remaining 6 children had causative genetic variants in the GLI2, PROP1, POU1F1, TBX3, PMM2, and GNAO1 genes, respectively. We elucidated the cause of CPHD in a fifth of the patients. Moreover, our study supports the PMM2 gene as a candidate gene for CPHD and suggests pathogenic variants in the GNAO1 gene as a potential novel genetic cause of CPHD.
- Publikační typ
- časopisecké články MeSH
