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
INTRODUCTION: Among children born small for gestational age, 10-15% fail to catch up and remain short (SGA-SS). The underlying mechanisms are mostly unknown. We aimed to decipher genetic aetiologies of SGA-SS within a large single-centre cohort. METHODS: Out of 820 patients treated with growth hormone (GH), 256 were classified as SGA-SS (birth length and/or birth weight <-2 SD for gestational age and life-minimum height <-2.5 SD). Those with the DNA triplet available (child and both parents) were included in the study (176/256). Targeted testing (karyotype/FISH/MLPA/specific Sanger sequencing) was performed if a specific genetic disorder was clinically suggestive. All remaining patients underwent MS-MLPA to identify Silver-Russell syndrome, and those with unknown genetic aetiology were subsequently examined using whole-exome sequencing or targeted panel of 398 growth-related genes. Genetic variants were classified using ACMG guidelines. RESULTS: The genetic aetiology was elucidated in 74/176 (42%) children. Of these, 12/74 (16%) had pathogenic or likely pathogenic (P/LP) gene variants affecting pituitary development (LHX4, OTX2, PROKR2, PTCH1, POU1F1), the GH-IGF-1 or IGF-2 axis (GHSR, IGFALS, IGF1R, STAT3, HMGA2), 2/74 (3%) the thyroid axis (TRHR, THRA), 17/74 (23%) the cartilaginous matrix (ACAN, various collagens, FLNB, MATN3), and 7/74 (9%) the paracrine chondrocyte regulation (FGFR3, FGFR2, NPR2). In 12/74 (16%), we revealed P/LP affecting fundamental intracellular/intranuclear processes (CDC42, KMT2D, LMNA, NSD1, PTPN11, SRCAP, SON, SOS1, SOX9, TLK2). SHOX deficiency was found in 7/74 (9%), Silver-Russell syndrome in 12/74 (16%) (11p15, UPD7), and miscellaneous chromosomal aberrations in 5/74 (7%) children. CONCLUSIONS: The high diagnostic yield sheds a new light on the genetic landscape of SGA-SS, with a central role for the growth plate with substantial contributions from the GH-IGF-1 and thyroid axes and intracellular regulation and signalling.
- MeSH
- dítě MeSH
- gestační stáří MeSH
- hypotrofický novorozenec MeSH
- insulinu podobný růstový faktor I MeSH
- lidé MeSH
- lidský růstový hormon * genetika MeSH
- nanismus * MeSH
- novorozenec MeSH
- poruchy růstu genetika diagnóza MeSH
- protein SHOX MeSH
- Silverův-Russellův syndrom * genetika MeSH
- tělesná výška genetika MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- novorozenec MeSH
- Publikační typ
- časopisecké články MeSH
MODY (Maturity-Onset Diabetes of the Young) představuje nejčastější formu monogenního diabetu. Genetické testování českých pacientů s klinickým podezřením na MODY začalo před 22 lety. Cílem studie bylo shrnout dosavadní nálezy. Klinická kritéria pro genetické testování MODY jsou věk v době diagnózy hyperglykemie do 35 let a absence pankreatických protilátek. Mezi podpůrná kritéria pro dospělé pacienty, z nichž alespoň některé musí být splněno, patří: výskyt diabetu ve více po sobě jdoucích generacích, detekovatelný C peptid několik let po diagnóze či absence známek metabolického syndromu. V českém registru pacientů suspektních na MODY evidujeme 1 788 rodin (3 539 osob), z nichž byla diagnóza MODY geneticky prokázána u 1 385 osob z 686 rodin (38%). Převažujícím podtypem (69%) byl glukokinázový diabetes (GCK-MODY) diagnostikovaný u 962 osob ze 473 rodin. Druhým nejčastějším podtypem MODY (16%) byl HNF1A-MODY nalezený u 111 rodin (233 osob). HNF4A-MODY představoval třetí nejčastější podtyp MODY (131 osob z 60 rodin, 9%). Zbývajících 6% potvrzených případů MODY (42 rodin) byly vzácné formy monogenního diabetu. Stanovení správné diagnózy MODY je zásadní pro pacienty a jejich rodiny, protože s sebou přináší možnost optimalizované, personalizované léčby.
Maturity-Onset Diabetes of the Young (MODY) represents the most frequent form of monogenic diabetes. Genetic testing of Czech patients with clinical suspicion on MODY began 22 years ago. The aim of the study was to describe the overall findings. Clinical criteria for genetic testing of MODY genes include age at diagnosis up to 35 years and absence of pancreatic antibodies. Supporting criteria, of which at least some must be fulfilled in adult probands, are positive family history of diabetes, detectable C-peptide several years after diagnosis and absence of metabolic syndrome. The Czech registry of MODY consists of 1,788 families (3,539 persons) of which MODY has been genetically clarified in 1,385 patients from 686 families (38%). Glucokinase diabetes (GCK-MODY) was the prevailing MODY subtype (69%) being diagnosed in 962 subjects from 473 families. The second most prevalent MODY subtype (16%) was HNF1A-MODY detected in 111 families (233 persons). HNF4A-MODY represented the third most prevalent subtype (131 persons, 60 families, 9%). The remaining 6% (42 families) of confirmed MODY represented rare forms of monogenic diabetes. Assessment of correct diagnosis of MODY is crucial for the patients and their families because it brings along tailored treatment options.
Familial short stature (FSS) describes vertically transmitted growth disorders. Traditionally, polygenic inheritance is presumed, but monogenic inheritance seems to occur more frequently than expected. Clinical predictors of monogenic FSS have not been elucidated. The aim of the study was to identify the monogenic etiology and its clinical predictors in FSS children. Of 747 patients treated with growth hormone (GH) in our center, 95 with FSS met the inclusion criteria (pretreatment height ≤-2 SD in child and his/her shorter parent); secondary short stature and Turner/Prader-Willi syndrome were excluded criteria. Genetic etiology was known in 11/95 children before the study, remaining 84 were examined by next-generation sequencing. The results were evaluated by American College of Medical Genetics and Genomics (ACMG) guidelines. Nonparametric tests evaluated differences between monogenic and non-monogenic FSS, an ROC curve estimated quantitative cutoffs for the predictors. Monogenic FSS was confirmed in 36/95 (38%) children. Of these, 29 (81%) carried a causative genetic variant affecting the growth plate, 4 (11%) a variant affecting GH-insulin-like growth factor 1 (IGF1) axis and 3 (8%) a variant in miscellaneous genes. Lower shorter parent's height (P = 0.015) and less delayed bone age (BA) before GH treatment (P = 0.026) predicted monogenic FSS. In children with BA delayed less than 0.4 years and with shorter parent's heights ≤-2.4 SD, monogenic FSS was revealed in 13/16 (81%) cases. To conclude, in FSS children treated with GH, a monogenic etiology is frequent, and gene variants affecting the growth plate are the most common. Shorter parent's height and BA are clinical predictors of monogenic FSS.
- Publikační typ
- časopisecké články MeSH
- Publikační typ
- abstrakt z konference MeSH
- Publikační typ
- abstrakt z konference MeSH
- MeSH
- autoprotilátky * MeSH
- diabetes mellitus 1. typu * genetika MeSH
- lidé MeSH
- mutace MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- komentáře MeSH
- práce podpořená grantem 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
- MeSH
- diabetes mellitus 2. typu * genetika MeSH
- hepatocytární jaderný faktor 1-alfa genetika MeSH
- hepatocytární jaderný faktor 4 genetika MeSH
- kohortové studie MeSH
- lidé MeSH
- mutace MeSH
- penetrance MeSH
- porodní hmotnost genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- dopisy MeSH
- práce podpořená grantem MeSH
Růst člověka je řízen z 80 % geneticky, jen 20 % se na něm podílejí vlivy prostředí. Pro růst jsou klíčové geny kódující proteohormony a podobné molekuly (růstový hormon, IGF-1, IGF-2, acidolabilní pojednotku ALS), hormonální receptory (receptor pro růstový hormon, pro IGF a pro spouštěcí hormony hypofýzy – GHRH a ghrelin) a v omezené míře enzymy (PAPPA 2). Důležité jsou geny pro transkripční faktory, které řídí morfogenezi (kaskáda sonic hedgehog a další) a diferenciaci adenohypofýzy (PROP1, POU1F1), ale také geny kódující transkripční faktory chondrocytů (SHOX). Ze strukturálních molekul jsou v popředí zájmu součásti chrupavčité mezibuněčné matrix (geny pro aggrecan, kolageny, matrilin, fibrilin a další). Spektrum genů zodpovědných jak za závažné růstové poruchy, tak za běžnou variabilitu růstu doplňují geny pro parakrinní signalizaci chondrocytu (systém FGFR3/NPR2), pro nitrobuněčnou signalizaci (Ras-MAPK kaskáda, JAK-STAT signalizační dráha) a pro fundamentální nitrobuněčné procesy, mezi které patří regulace epigenetických modifikací DNA a kontrola integrity DNA. Genetické testování má dvojí smysl: okamžitý, protože přináší důležitou informaci pro pacienta a jeho rodinu o podstatě odchylky, o jejím budoucím vývoji a o dědičném přenosu – a dlouhodobý, protože pomáhá porozumět mechanismu nemoci a navrhovat nové terapie.
Determination of human growth is mostly genetic (80%) and only partially environmental (20%). The key genes regulating growth include genes encoding proteohormones a related molecules (growth hormone, IGF-1, IGF-2, acid-lable subunit ALS), hormonal receptors (receptors for growth hormone, IGF and pituitary releasing hormones – GHRH and ghrelin), with a limited role of enzymes (PAPPA 2). Genes encoding transcription factors regulate pituitary morphogenesis (sonic hedgehog cascade and others) and differentiation (PROP1, POU1F1) and also chondrocytes (SHOX). Structural molecules include components of cartilagineous extracellular matrix (gens encoding aggrecan, collagens, matrillin, fibrillin and others). The spectrum of genes responsible for both severe growth failure and minor variability of height includes genes for paracrine chondrocyte signalisation (FGFR3/NPR2 system), for intracellular signalisation (Ras-MAPK cascade, JAK-STAT signalling pathway) and for fundamental intracellular processes – regulation of DNA epigenetic modifications and control of DNA integrity. Genetic testing offers dual benefits: Immediate, as it bears an important information for the patient and his/her family about the disease nature, its future outcome and its inheritance – and a long-term – each testing contributes to understanding of disease mechanisms and to proposing novel therapies.
- MeSH
- dítě MeSH
- embryonální a fetální vývoj genetika MeSH
- genetické testování MeSH
- hypofýza abnormality embryologie MeSH
- lidé MeSH
- lidský růstový hormon nedostatek MeSH
- mutace genetika MeSH
- poruchy růstu * etiologie genetika patologie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
