PURPOSE: Genetic testing in consanguineous families advances the general comprehension of pathophysiological pathways. However, short stature (SS) genetics remain unexplored in a defined consanguineous cohort. This study examines a unique pediatric cohort from Sulaimani, Iraq, aiming to inspire a genetic testing algorithm for similar populations. METHODS: Among 280 SS referrals from 2018-2020, 64 children met inclusion criteria (from consanguineous families; height ≤ -2.25 SD), 51 provided informed consent (30 females; 31 syndromic SS) and underwent investigation, primarily via exome sequencing. Prioritized variants were evaluated by the American College of Medical Genetics and Genomics standards. A comparative analysis was conducted by juxtaposing our findings against published gene panels for SS. RESULTS: A genetic cause of SS was elucidated in 31 of 51 (61%) participants. Pathogenic variants were found in genes involved in the GH-IGF-1 axis (GHR and SOX3), thyroid axis (TSHR), growth plate (CTSK, COL1A2, COL10A1, DYM, FN1, LTBP3, MMP13, NPR2, and SHOX), signal transduction (PTPN11), DNA/RNA replication (DNAJC21, GZF1, and LIG4), cytoskeletal structure (CCDC8, FLNA, and PCNT), transmembrane transport (SLC34A3 and SLC7A7), enzyme coding (CYP27B1, GALNS, and GNPTG), and ciliogenesis (CFAP410). Two additional participants had Silver-Russell syndrome and 1 had del22q.11.21. Syndromic SS was predictive in identifying a monogenic condition. Using a gene panel would yield positive results in only 10% to 33% of cases. CONCLUSION: A tailored testing strategy is essential to increase diagnostic yield in children with SS from consanguineous populations.
- MeSH
- algoritmy MeSH
- dítě MeSH
- genetické testování * metody MeSH
- lidé MeSH
- mladiství MeSH
- mutace genetika MeSH
- nanismus genetika diagnóza MeSH
- pokrevní příbuzenství * MeSH
- poruchy růstu genetika diagnóza MeSH
- předškolní dítě MeSH
- rodokmen MeSH
- sekvenování exomu metody 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
- Geografické názvy
- Irák MeSH
INTRODUCTION: Pigmented hypertrichosis with insulin-dependent diabetes mellitus (PHID) syndrome is a rare disease, and part of the cluster histiocytosis-lymphadenopathy plus syndrome (H syndrome), which is associated with mutations in the SLC29A3 gene. Patients with PHID show clinical features of H syndrome but also have insulin-dependent diabetes mellitus. The PHID has previously been described as predominantly in absence of pancreatic autoantibodies. Case Series Presentation: Through an open call in two international diabetes registers, clinical and genetic characteristics of 7 PHID patients in 6 treatment centres were collected after informed consent. All of them had consanguinity in their families, and their origins were located in North-African and Middle Eastern regions. Four out of 7 patients had at least one positive pancreatic autoantibody. DISCUSSION AND CONCLUSION: Our case series reveals that PHID exhibits a wide range of clinical symptoms and signs. When consanguinity is present in a patient with newly diagnosed diabetes, and/or if other atypical symptoms such as dysmorphic features, skin lesions, haematological abnormalities, and developmental delay are present, threshold for genetic analysis should be low. Moreover, the presence of autoantibodies should not withhold genetic testing as our case series contradicts the previous observation of predominant autoantibody absence in PHID.
- MeSH
- autoprotilátky krev imunologie MeSH
- diabetes mellitus 1. typu * genetika komplikace MeSH
- dítě MeSH
- hypertrichóza * genetika MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mutace MeSH
- pokrevní příbuzenství MeSH
- předškolní dítě MeSH
- proteiny přenášející nukleosidy genetika MeSH
- syndrom 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
- kazuistiky 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
The immunogenome is the part of the genome that underlies immune mechanisms and evolves under various selective pressures. Two complex regions of the immunogenome, major histocompatibility complex (MHC) and natural killer cell receptor (NKR) genes, play an important role in the response to selective pressures of pathogens. Their importance is expressed by their genetic polymorphism at the molecular level, and their diversity associated with different types of diseases at the population level. Findings of associations between specific combinations of MHC/NKR haplotypes with different diseases in model species suggest that these gene complexes did not evolve independently. No such associations have been described in horses so far. The aim of the study was to detect associations between MHC and NKR gene/microsatellite haplotypes in three horse breed groups (Camargue, African, and Romanian) by statistical methods; chi-square test, Fisher's exact test, Pearson's goodness-of-fit test and logistic regression. Associations were detected for both MHC/NKR genes and microsatellites; the most significant associations were found between the most variable KLRA3 gene and the EQCA-1 or EQCA-2 genes. This finding supports the assumption that the KLRA3 is an important receptor for MHC I and that interactions of these molecules play important roles in the horse immunity and reproduction. Despite some limitations of the study such as low numbers of horses or lack of knowledge of the selected genes functions, the results were consistent across different statistical methods and remained significant even after overconservative Bonferroni corrections. We therefore consider them biologically plausible.
- MeSH
- databáze genetické klasifikace MeSH
- dědičnost genetika MeSH
- DNA * analýza genetika MeSH
- genetické testování metody MeSH
- lidé MeSH
- ochrana genetických informací etika MeSH
- pokrevní příbuzenství * MeSH
- sekvenování celého genomu metody MeSH
- zločinci MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Gene flow between species in the genus Arabidopsis occurs in significant amounts, but how exactly gene flow is achieved is not well understood. Polyploidization may be one avenue to explain gene flow between species. One problem, however, with polyploidization as a satisfying explanation is the occurrence of lethal genomic instabilities in neopolyploids as a result of genomic exchange, erratic meiotic behavior, and genomic shock. We have created an autoallohexaploid by pollinating naturally co-occurring diploid Arabidopsis thaliana with allotetraploid Arabidopsis suecica (an allotetraploid composed of A. thaliana and Arabidopsis arenosa). Its triploid offspring underwent spontaneous genome duplication and was used to generate a multigenerational pedigree. Using genome resequencing, we show that 2 major mechanisms promote stable genomic exchange in this population. Legitimate meiotic recombination and chromosome segregation between the autopolyploid chromosomes of the 2 A. thaliana genomes occur without any obvious bias for the parental origin and combine the A. thaliana haplotypes from the A. thaliana parent with the A. thaliana haplotypes from A. suecica similar to purely autopolyploid plants. In addition, we repeatedly observed that occasional exchanges between regions of the homoeologous chromosomes are tolerated. The combination of these mechanisms may result in gene flow leading to stable introgression in natural populations. Unlike the previously reported resynthesized neoallotetraploid A. suecica, this population of autoallohexaploids contains mostly vigorous, and genetically, cytotypically, and phenotypically variable individuals. We propose that naturally formed autoallohexaploid populations might serve as an intermediate bridge between diploid and polyploid species, which can facilitate gene flow rapidly and efficiently.
- MeSH
- pokrevní příbuzenství MeSH
- transplantace jater * MeSH
- žijící dárci MeSH
- Publikační typ
- rozhovory MeSH
Consanguineous families have often played a role in the discovery of novel genes, especially in paediatric endocrinology. At this time, it has been estimated that over 8.5% of all children worldwide have consanguineous parents. Consanguinity is linked to demographic, cultural, and religious practises and is more common in some areas around the world than others. In children with endocrine conditions from consanguineous families, there is a greater probability that a single-gene condition with autosomal recessive inheritance is causative. From 1966 and the first description of Laron syndrome, through the discovery of the first KATP channel genes ABCC8 and KCNJ11 causing congenital hyperinsulinism (CHI) in the 1990s, to recent discoveries of mutations in YIPF5 as the first cause of monogenic diabetes due to the disruption of the endoplasmic reticulum (ER)-to-Golgi trafficking in the β-cell and increased ER stress; positive genetic findings in children from consanguinity have been important in elucidating novel genes and mechanisms of disease, thereby expanding knowledge into disease pathophysiology. The aim of this narrative review was to shed light on the lessons learned from consanguineous pedigrees with the help of 3 fundamental endocrine conditions that represent an evolving spectrum of pathophysiological complexity - from CHI, a typically single-cell condition, to monogenic diabetes which presents with uniform biochemical parameters (hyperglycaemia and glycosuria), despite varying aetiologies, up to the genetic regulation of human growth - the most complex developmental phenomenon.
- MeSH
- diabetes mellitus * genetika MeSH
- dítě MeSH
- KATP kanály genetika MeSH
- lidé MeSH
- mutace MeSH
- nanismus * MeSH
- pokrevní příbuzenství MeSH
- vrozený hyperinzulinismus * genetika MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Dog attacks on children are a widespread problem, which can occur when parents fail to realise a potentially dangerous interaction between a dog and a child. The aim of the study was to evaluate the ability of parents to identify dangerous situations from several everyday child-dog interactions and to determine whether the participants connected these situations to a particular breed of dog. Five sets of photographs depicting potentially dangerous interactions from everyday situations between children and three dogs (one of each breed) were presented via an online survey to parents of children no more than 6 years old. Data from 207 respondents were analysed using proc GLIMMIX in SAS program, version 9.3. The probability of risk assessment varied according to dog breed (p < 0.001) as well as to the depicted situation (p < 0.001). Results indicated that Labrador Retriever was considered the least likely of the three dogs to be involved in a dangerous dog-child interaction (with 49% predicting a dangerous interaction), followed by Parson Russell Terrier (63.2%) and American Pit Bull Terrier (65%). Participants considered one particular dog-child interaction named 'touching a bowl' a dangerous interaction at a high rate (77.9%) when compared with the other presented situations, which were assessed as dangerous at rates of 48.4% to 56.5%. The breed of dog seems to be an influential factor when assessing a potentially dangerous outcome from a dog-child interaction. Contrary to our hypothesis, interactions involving the small dog (Russell Terrier) were rated more critically, similarly to those of the Pit Bull Terrier. These results suggest that even popular family dog breeds, such as Labrador Retrievers, should be treated with more caution.
- MeSH
- chov MeSH
- kousnutí a bodnutí * MeSH
- nebezpečné chování MeSH
- průzkumy a dotazníky MeSH
- psi MeSH
- rodina MeSH
- zvířata MeSH
- Check Tag
- psi MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
