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
- MeSH
- genetické testování * metody MeSH
- lidé MeSH
- manželství zákonodárství a právo MeSH
- pokrevní příbuzenství * MeSH
- vrozené vady MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
- 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
- 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
The evaluation of frontal sinus similarity is one way to detect biological relationships, especially in small groups, including families of historically known personalities. However, possibilities for studying this issue are currently limited. This contribution deals with the frontal sinuses of a rare osteological sample with known genealogical data, members of the noble Swéerts-Sporck family from the 17th to 20th centuries. The aim is to verify whether the frontal sinuses reflect documented family relationships. Basic dimensions of the frontal sinus such as total surface area and volume, and maximum height and width, and also morphology and anatomical features were evaluated using computed tomography scans. The portions of the frontal sinus above the "external supraorbital line" were analyzed. The degree of similarity between biologically related individuals was determined for each variable and compared with their known biological distance. The degree of similarity based on dimensions was evaluated using both the unadjusted measured data and standardized data adjusted to size. For the unadjusted dimensions, a positive correlation between morphological similarity and biological relatedness was apparent. On the other hand, no positive correlation was apparent for most of the standardized data. Only total volume showed a very weak indication of a positive trend in the standardized data, but this was weaker than in the original values. A positive quantifiable relationship between morphological patterns and biological distance is not clearly indicated. However, nonmetric features do support the documented relationships of the individuals.
Vyhýbání se sexu s příbuznými neboli incestu je považováno za univerzální jev. Jednotlivé obory se však liší vysvětlením vzniku zábrany incestu. Cílem této přehledové studie je představit teorie vyhýbání se incestu z perspektivy kulturní a evoluční antropologie, a přispět tak k pochopení komplexity celé problematiky. Důvodem nízkého výskytu incestu může být existence incestního tabu, představující ustanovené společenské normy a zvyklosti, které incestu zabraňují. Univerzalita incestního tabu se však týká pouze nukleární rodiny, pro širší příbuzenstvo je vysoce kulturně variabilní. Nízký výskyt incestu může být také důsledkem tzv. Westermarckova efektu, při němž dochází ke vzniku sexuální averze mezi jedinci, kteří spolu vyrůstali (tj. obvykle příbuzní jedinci). Empirické studie ukazují, že jedinci, kteří spolu vyrůstali v úzkém kontaktu zhruba do 6 let věku se vzájemně sexuálně nepřitahují. V závěru navrhujeme rozlišovat mezi sexuální indiferencí (tj. absencí přitažlivosti) vůči příbuzným v běžných sociálních interakcích a sexuální averzí, která je specifická pro sexuální kontext.
Avoiding sex with relatives alias incest is considered to be a universal phenomenon. Individual disciplines, however, differ in their explanation of the emergence of incest avoidance. This review aims to introduce the theories of incest avoidance from the point of view of cultural and evolutionary anthropology and thus contribute to the understanding of the complex phenomenon. The reason for the low occurrence of incest might be the existence of the incest taboo – the established social norms and conventions that prevent incest. However, the universality of the incest taboo is limited only to the nuclear family; the incest taboo with respect to wider kin has high cultural variability. The low occurrence of incest might also be a consequence of the so-called Werstermarck effect, i.e., the emergence of sexual aversion among individuals that grew up together (usually relatives), empirical studies show that individuals that grew up together in close contact until approximately six years old are not attracted to each other. Therefore, we conclude that it is important to distinguish between sexual indifference (i.e., the absence of attractivity) towards relatives in daily social interactions and sexual aversion specific to a sexual context.
