Paediatric diabetes subtypes in a consanguineous population: a single-centre cohort study from Kurdistan, Iraq.

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.

Choledochal Cyst with 17q12 Chromosomal Duplication.

The 17q12 chromosomal region carries the HNF1B gene, mutations of which cause various conditions. When searching for HNF1B/17q12 rearrangements among children with biliary atresia and/or choledochal cysts, we identified a male proband carrying a 17q12 duplication spanning 1698 kb that included 24 genes from TBC1D3C to HNF1B. The boy presented with cholestatic jaundice at the age of 2 weeks due to a choledochal cyst sized 15 ×12 mm (type Ia according to the Todani classification). He underwent a shunt surgery consisting of a hepaticojejunostomy using Roux-en-Y loop at the age of 2 months, which led to a permanent relief of cholestasis. Perioperative liver histology revealed significant hepatic fibrosis and bile ductular proliferation. At 17 years, he has a mildly enlarged liver with decreased elasticity, an upper-normal-sized spleen, normal biochemistry values, and no renal or hepatic cysts. We report the first hepatobiliary phenotype in a patient with an HNF1B overdosage.

Combined pituitary hormone deficiency due to gross deletions in the POU1F1 (PIT-1) and PROP1 genes.

Pituitary development depends on a complex cascade of interacting transcription factors and signaling molecules. Lesions in this cascade lead to isolated or combined pituitary hormone deficiency (CPHD). The aim of this study was to identify copy number variants (CNVs) in genes known to cause CPHD and to determine their structure. We analyzed 70 CPHD patients from 64 families. Deletions were found in three Turkish families and one family from northern Iraq. In one family we identified a 4.96 kb deletion that comprises the first two exons of POU1F1. In three families a homozygous 15.9 kb deletion including complete PROP1 was discovered. Breakpoints map within highly homologous AluY sequences. Haplotype analysis revealed a shared haplotype of 350 kb among PROP1 deletion carriers. For the first time we were able to assign the boundaries of a previously reported PROP1 deletion. This gross deletion shows strong evidence to originate from a common ancestor in patients with Kurdish descent. No CNVs within LHX3, LHX4, HESX1, GH1 and GHRHR were found. Our data prove multiplex ligation-dependent probe amplification to be a valuable tool for the detection of CNVs as cause of pituitary insufficiencies and should be considered as an analytical method particularly in Kurdish patients.

De novo mutations of GCK, HNF1A and HNF4A may be more frequent in MODY than previously assumed.

AIMS/HYPOTHESIS: MODY is mainly characterised by an early onset of diabetes and a positive family history of diabetes with an autosomal dominant mode of inheritance. However, de novo mutations have been reported anecdotally. The aim of this study was to systematically revisit a large collection of MODY patients to determine the minimum prevalence of de novo mutations in the most prevalent MODY genes (i.e. GCK, HNF1A, HNF4A). METHODS: Analysis of 922 patients from two national MODY centres (Slovakia and the Czech Republic) identified 150 probands (16%) who came from pedigrees that did not fulfil the criterion of two generations with diabetes but did fulfil the remaining criteria. The GCK, HNF1A and HNF4A genes were analysed by direct sequencing. RESULTS: Mutations in GCK, HNF1A or HNF4A genes were detected in 58 of 150 individuals. Parents of 28 probands were unavailable for further analysis, and in 19 probands the mutation was inherited from an asymptomatic parent. In 11 probands the mutations arose de novo. CONCLUSIONS/INTERPRETATION: In our cohort of MODY patients from two national centres the de novo mutations in GCK, HNF1A and HNF4A were present in 7.3% of the 150 families without a history of diabetes and 1.2% of all of the referrals for MODY testing. This is the largest collection of de novo MODY mutations to date, and our findings indicate a much higher frequency of de novo mutations than previously assumed. Therefore, genetic testing of MODY could be considered for carefully selected individuals without a family history of diabetes.

[Liver, kidneys and diabetes: three faces of HNF1B gene deficit]. / Játra, ledviny a diabetes: tri tváre deficitu genu HNF1B.

The renal cysts and diabetes syndrome (RCAD), also known as HNF1B-MODYor MODY5, is caused by the deletion or point mutation of HNF1B gene which leads to the depletion of HNF1B transcription factor. The main clinical components of RCAD include cystic kidney disease or other developmental anomalies of the kidneys and diabetes mellitus which typically manifests in the second decade of life or later. Renal disorders may lead to the development of chronic renal insufficiency already in childhood or young adulthood. The other symptoms include hepatic impairment - cholestatic jaundice in middle-aged patients, sometimes even neonatal cholestasis, atrophy of the pancreas with the impairment of exocrine pancreatic secretion and some congenital anomalies of the genital tract. As opposed to the other forms of MODY diabetes, the family history may not be positive because most of the deviations of HNF1B appear de novo. We associate RCAD in particular with adults suffering from diabetes and cystic kidney disease and/or cholestatic jaundice and children with cystic kidney disease of unclear etiology, even without the presence of diabetes. A supportive finding may be hypomagnesemia which occurs in up to 70 % of patients diagnosed with HNF1B related disease and hyperuricemia.Key words: HNF1B - MODY - RCAD - diabetes mellitus - cholestatic jaundice.

Integrative Role of the SALL4 Gene: From Thalidomide Embryopathy to Genetic Defects of the Upper Limb, Internal Organs, Cerebral Midline, and Pituitary.

BACKGROUND: The thalidomide disaster resulted in tremendous congenital malformations in more than 10,000 children in the late 1950s and early 1960s. SUMMARY: Although numerous putative mechanisms were proposed to explain thalidomide teratogenicity, it was confirmed only recently that thalidomide, rather its derivative 5-hydroxythalidomide (5HT) in a complex with the cereblon protein, interferes with early embryonic transcriptional regulation. 5HT induces selective degradation of SALL4, a principal transcriptional factor of early embryogenesis. Genetic syndromes caused by pathogenic variants of the SALL4 gene phenocopy thalidomide embryopathy with congenital malformations ranging from phocomelia, reduced radial ray, to defects of the heart, kidneys, ear, eye, and possibly cerebral midline and pituitary. SALL4 interacts with TBX5 and a handful of other transcriptional regulators and downregulates the Sonic hedgehog signaling pathway. Cranial midline defects, microcephaly, and short stature due to growth hormone deficiency have been occasionally reported in children carrying SALL4 pathogenic variants associated with generalized stunting of growth rather than just the loss of height attributable to the shortening of leg bones in many children with thalidomide embryopathy. KEY MESSAGES: Thus, SALL4 joins the candidate gene list for monogenic syndromic pituitary insufficiency. In this review, we summarize the journey from the thalidomide disaster through the functions of the SALL4 gene to its link to the hormonal regulation of growth.

SALL4 Phenotype in Four Generations of One Family: An Interplay of the Upper Limb, Kidneys, and the Pituitary.

INTRODUCTION: The SALL4 gene encodes a transcription factor that is essential for early embryonic cellular differentiation of the epiblast and primitive endoderm. It is required for the development of neural tissue, kidney, heart, and limbs. Pathogenic SALL4 variants cause Duane-radial ray syndrome (Okihiro syndrome), acro-renal-ocular syndrome, and Holt-Oram syndrome. We report a family with vertical transmission of a SALL4 pathogenic variant leading to radial hypoplasia and kidney dystopia in several generations with additional growth hormone deficiency (GHD) in the proband. CASE PRESENTATION: Our male proband was born at the 39th week of gestation. He was born small for gestational age (SGA; birth weight 2,550 g, -2.2 SDS; length 47 cm, -2.0 SDS). He had bilateral asymmetrical radial ray malformation (consisting of radial hypoplasia, ulnar flexure, and bilateral aplasia of the thumb) and pelvic kidney dystopia, but no cardiac malformations, clubfoot, ocular coloboma, or Duane anomaly. He was examined for progressive short stature at the age of 3.9 years, where his IGF-1 was 68 µg/L (-1.0 SD), and growth hormone (GH) after stimulation 6.2 µg/L. Other pituitary hormones were normal. A brain CT revealed normal morphology of the cerebral midline and the pituitary. He had a dental anomaly - a central mandibular ectopic canine. MRI could not be done due to the presence of metal after multiple corrective plastic surgeries of his hands. His mother's and father's heights are 152.3 cm (-2.4 SD) and 177.8 cm (-0.4 SD), respectively. His father has a milder malformation of the forearm. The affected paternal grandfather (height 164 cm; -2.3 SD) has a radial ray defect with missing opposition of the thumb. The family reports a similar phenotype of radial dysplasia in the paternal grandfather's mother. The proband started GH therapy at age 6.5 years when his height was 109 cm (-2.8 SDS) and he experienced catch-up growth as expected in GHD. Puberty started spontaneously at the age of 12.5 years. At age 13, his height was 158.7 cm (-0.2 SDS). Whole-exome sequencing revealed a nonsense variant in the SALL4 gene c.1717C>T (p.Arg573Ter) in the proband, his father, and paternal grandfather. CONCLUSION: This is the first observation of a patient with a congenital upper limb defect due to a pathogenic SALL4 variant who has isolated GHD with no apparent cerebral or facial midline anomaly and has been successfully treated with growth hormone.

The Genetic Landscape of Children Born Small for Gestational Age with Persistent Short Stature.

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.

Genetic testing of children with familial tall stature: is it worth doing?

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. OBJECTIVES: To elucidate the genetic etiology in families with FTS and to describe their phenotype in detail. DESIGN, SETTINGS AND PATIENTS: Children with FTS (height in both the child and his/her taller parent >2 SD) referred to the Endocrinology center of Motol University Hospital were enrolled to the study. Their DNA was examined cytogenetically and via 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 sings 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.

Molecular mechanism of HNF-1A-mediated HNF4A gene regulation and promoter-driven HNF4A-MODY diabetes.

Monogenic diabetes is a gateway to precision medicine through molecular mechanistic insight. Hepatocyte nuclear factor 1A (HNF-1A) and HNF-4A are transcription factors that engage in crossregulatory gene transcription networks to maintain glucose-stimulated insulin secretion in pancreatic ß cells. Variants in the HNF1A and HNF4A genes are associated with maturity-onset diabetes of the young (MODY). Here, we explored 4 variants in the P2-HNF4A promoter region: 3 in the HNF-1A binding site and 1 close to the site, which were identified in 63 individuals from 21 families of different MODY disease registries across Europe. Our goal was to study the disease causality for these variants and to investigate diabetes mechanisms on the molecular level. We solved a crystal structure of HNF-1A bound to the P2-HNF4A promoter and established a set of techniques to probe HNF-1A binding and transcriptional activity toward different promoter variants. We used isothermal titration calorimetry, biolayer interferometry, x-ray crystallography, and transactivation assays, which revealed changes in HNF-1A binding or transcriptional activities for all 4 P2-HNF4A variants. Our results suggest distinct disease mechanisms of the promoter variants, which can be correlated with clinical phenotype, such as age of diagnosis of diabetes, and be important tools for clinical utility in precision medicine.

Analysis of children with familial short stature: who should be indicated for genetic testing?

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.

SNPman: a program for genotype calling using run data from TaqMan allelic discrimination.

SUMMARY: The SNPman program calls the genotypes of single nucleotide polymorphisms (SNP) from TaqMan allelic discrimination assays. It utilizes the fluorescence data collected over the whole PCR run, rather than relying on the end point fluorescence measurements that is the basis of the genotype calling process in most software solutions sold with the real-time instruments. This inspection of run data facilitates genotype calls in difficult sample sets, especially in those containing various concentrations of DNA or inhibitors, as indicated by results of a reanalysis of 3738 genotyping samples. The program works with data from three different widely used PCR instruments. AVAILABILITY: The compiled program is available online at http://sourceforge.net/projects/snpman/files/, along with its user documentation and demonstration data files. It is free of charge for non-commercial users. CONTACT: Ondrej.Cinek@Lfmotol.cuni.cz SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Ancestral mutations may cause a significant proportion of GCK-MODY.

BACKGROUND: Although the literature indicates that ancestral mutations in the glucokinase (GCK) gene are rare, we have detected a high frequency of four prevalent mutations that together are responsible for over one third of the GCK mutations in our Czech National Register of monogenic diabetes. Therefore, we studied their potential ancestral origin in our and neighbouring Polish populations. METHODS: We analysed the lineage of four mutations in the GCK gene - p.Glu40Lys (21 apparently unrelated families), p.Leu315His (15 families), p.Gly318Arg (26 families), and p.Val33Ala (10 families) - using genotypes of 16 single nucleotide polymorphisms that span a 14 Mb region around the gene. Haplotypes were reconstructed using Phase and Haploview programmes, and their age was estimated using dmle+. RESULTS: We found strong evidence that supports ancestral origin of three of the four mutations: the p.Glu40Lys mutation was associated with an 11-marker long conserved haplotype, the p.Leu315His mutation was associated with a 7-marker haplotype, and the p.Gly318Arg mutation was associated with an 8-marker haplotype. None of these haplotypes were detected in the general population with a frequency >0.5%. The ages of the mutations were roughly estimated to be between 82 and 110 generations old (95% credible sets 65-151). The fourth prevalent mutation, p.Val33Ala, lacked statistically significant evidence for the founder effect, although there were some indications for its common origin. CONCLUSIONS: The large proportion of families carrying three ancestral mutations in GCK indicates that the previously assumed rarity of the founder effect with regard to GCK-maturity onset diabetes of the young (MODY) should be reconsidered.

Invaluable Role of Consanguinity in Providing Insight into Paediatric Endocrine Conditions: Lessons Learnt from Congenital Hyperinsulinism, Monogenic Diabetes, and Short Stature.

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 ß-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.

Search for a time- and cost-saving genetic testing strategy for maturity-onset diabetes of the young.

AIMS: Correct genetic diagnosis of maturity-onset diabetes of the young (MODY) is beneficial for person's diabetes management compared to no genetic testing. Aim of the present study was a search for optimal time- and cost-saving strategies by comparing two approaches of genetic testing of participants with clinical suspicion of MODY. METHODS: A total of 121 consecutive probands referred for suspicion of MODY (Group A) were screened using targeted NGS (tNGS), while the other 112 consecutive probands (Group B) underwent a single gene test based on phenotype, and in cases of negative findings, tNGS was conducted. The study was performed in two subsequent years. The genetic results, time until reporting of the final results and financial expenses were compared between the groups. RESULTS: MODY was confirmed in 30.6% and 40.2% probands from Groups A and B, respectively; GCK-MODY was predominant (72.2% in Group A and 77.8% in Group B). The median number of days until results reporting was 184 days (IQR 122-258) in Group A and 91 days (44-174) in Group B (p < 0.00001). Mean costs per person were higher for Group A (639 ± 30 USD) than for Group B (584 ± 296 USD; p = 0.044). CONCLUSIONS: The two-step approach represented a better strategy for genetic investigation of MODY concerning time and costs compared to direct tNGS. Although a single-gene investigation clarified the diabetes aetiology in the majority of cases, tNGS could reveal rare causes of MODY and expose possible limitations of both standard genetic techniques and clinical evaluation.

Quality of Life and Treatment Satisfaction in Participants with Maturity-Onset Diabetes of the Young: A Comparison to Other Major Forms of Diabetes.

AIMS: We investigated the quality of life (QoL), treatment satisfaction and perception of genetic results in participants with Maturity-Onset Diabetes of the Young (MODY) and compared the results with those of subjects with type 1 (T1D) or type 2 (T2D) diabetes. METHODS: A total of 162 adults with GCK-MODY, 62 with HNF1A-MODY and 29 with HNF4A-MODY answered the questionnaire Audit of Diabetes Dependent Quality of Life, the Diabetes Treatment Satisfaction Questionnaire and non-validated instrument examining the respondent's perception of the genetic results. Data from GCK-MODY patients were compared with 84 participants with T2D and HNF-MODY subjects were compared with 81 participants having T1D. RESULTS: Higher age (p=0.004), higher haemoglobin A1c (p=0.026) and medication (p=0.019) were associated with lower general QoL in GCK-MODY patients. In HNF-MODY patients, lower general QoL was associated with a longer time since diagnosis (p=0.005), worse haemoglobin bA1c (p=0.006) and insulin treatment (p=0.019). Similar numbers of participants with GCK- and HNF-MODY considered the genetic diagnosis of MODY to be positive, negative and without significance. The patient with GCK-MODY did not differ from those with T2D in terms of their QoL, but they were less satisfied with their treatment (p<0.001). QoL was better in patients with HNF-MODY compared with patients with T1D (p=0.006), and they did not differ in terms of treatment satisfaction. CONCLUSIONS: QoL was affected in both GCK-MODY and HNF-MODY subjects. Apprehension of genetic diagnosis was not single-valued in MODY respondents.

Two New Mutations in the CEL Gene Causing Diabetes and Hereditary Pancreatitis: How to Correctly Identify MODY8 Cases.

CONTEXT: Maturity onset diabetes of the young, type 8 (MODY8) is associated with mutations in the CEL gene, which encodes the digestive enzyme carboxyl ester lipase. Several diabetes cases and families have in recent years been attributed to mutations in CEL without any functional or clinical evidence provided. OBJECTIVE: To facilitate correct MODY8 diagnostics, we screened 2 cohorts of diabetes patients and delineated the phenotype. METHODS: Young, lean Swedish and Finnish patients with a diagnosis of type 2 diabetes (352 cases, 406 controls) were screened for mutations in the CEL gene. We also screened 58 Czech MODY cases who had tested negative for common MODY genes. For CEL mutation-positive subjects, family history was recorded, and clinical investigations and pancreatic imaging performed. RESULTS: Two cases (1 Swedish and 1 Czech) with germline mutation in CEL were identified. Clinical and radiological investigations of these 2 probands and their families revealed dominantly inherited insulin-dependent diabetes, pancreatic exocrine dysfunction, and atrophic pancreas with lipomatosis and cysts. Notably, hereditary pancreatitis was the predominant phenotype in 1 pedigree. Both families carried single-base pair deletions in the proximal part of the CEL variable number of tandem repeat (VNTR) region in exon 11. The mutations are predicted to lead to aberrant protein tails that make the CEL protein susceptible to aggregation. CONCLUSION: The diagnosis of MODY8 requires a pancreatic exocrine phenotype and a deletion in the CEL VNTR in addition to dominantly inherited diabetes. CEL screening may be warranted also in families with hereditary pancreatitis of unknown genetic etiology.

Isolated growth hormone deficiency in children with vertically transmitted short stature: What do the genes tell us?

Introduction: The growth hormone deficiency (GHD) diagnosis is controversial especially due to low specificity of growth hormone (GH) stimulation tests. It is therefore believed that children diagnosed with GHD form a heterogeneous group with growth disorder frequently independent on GH function. No study evaluating the complex etiology of growth failure in children with diagnosed GHD has been performed thus far. Aims: To discover genetic etiology of short stature in children with diagnosed GHD from families with short stature. Methods: Fifty-two children diagnosed with primary GHD and vertically transmitted short stature (height SDS in the child and his/her shorter parent <-2 SD) were included to our study. The GHD diagnosis was based on growth data suggestive of GHD, absence of substantial disproportionality (sitting height to total height ratio <-2 SD or >+2 SD), IGF-1 levels <0 for age and sex specific SD and peak GH concentration <10 ug/L in two stimulation tests. All children were examined using next-generation sequencing methods, and the genetic variants were subsequently evaluated by American College of Medical Genetics standards and guidelines. Results: The age of children at enrollment into the study was 11 years (median, IQR 9-14 years), their height prior to GH treatment was -3.0 SD (-3.6 to -2.8 SD), IGF-1 concentration -1.4 SD (-2.0 to -1.1 SD), and maximal stimulated GH 6.3 ug/L (4.8-7.6 ug/L). No child had multiple pituitary hormone deficiency or a midbrain region pathology. Causative variant in a gene that affects growth was discovered in 15/52 (29%) children. Of them, only 2 (13%) had a genetic variant affecting GH secretion or function (GHSR and OTX2). Interestingly, in 10 (67%) children we discovered a primary growth plate disorder (ACAN, COL1A2, COL11A1, COL2A1, EXT2, FGFR3, NF1, NPR2, PTPN11 [2x]), in one (7%) a genetic variant impairing IGF-1 action (IGFALS) and in two (12%) a variant in miscellaneous genes (SALL4, MBTPS2). Conclusions: In children with vertically transmitted short stature, genetic results frequently did not correspond with the clinical diagnosis of GH deficiency. These results underline the doubtful reliability of methods standardly used to diagnose GH deficiency.

Familial mild hyperglycemia associated with a novel ABCC8-V84I mutation within three generations.

We present a unique case of a 19-year-old man with a positive family history of persistent mild hyperglycemia and a novel V84I mutation in ABCC8. The proband was initially detected to have fasting hyperglycemia (ranging 6.1-6.4 mmol/L) at the age of 12 years. Increased fasting blood glucose was also subsequently detected in five additional family members (in his twin brother, sister, mother, maternal aunt, and grandfather). The grandfather has been known to have mild diabetes since 30 years and has never been treated. After having excluded a causative mutation in five maturity-onset diabetes of the young genes (MODY1-4 and 6), we identified a novel ABCC8 V84I mutation, which segregated with autosomal dominant transmission of mild hyperglycemia within three generations. This mutation that is located in a conserved area of transmembrane domain TMD0 seems to be a rare cause of clinical phenotype resembling glucokinase-deficient diabetes.