17q12 deletion syndrome is a chromosomal abnormality, where there is a small missing piece (deletion) of genetic material on the long arm (q) of chromosome 17. Sign and symptoms can vary widely among different patients. Recently, a patient was diagnosed with 17q12 deletion syndrome in our hospital, and the clinical characteristics presented as absence of the right kidney, compensatory hypertrophy of the left kidney, multiple small cysts in the left kidney, pancreatic atrophy, hypomagnesemia, bowed uterus, multiple follicular cysts in both lobes of the thyroid gland, and maturity-onset diabetes of the young type 5 (MODY-5). A 1.5-Mb deletion with haploinsufficiency for 20 genes within the 17q12 region was found through copy number variation (CNV) analysis based on metagenomic next-generation sequencing (mNGS) technology. In addition to HNF1B absence, the LIM-class homeobox 1 transcription factor (LHX1) and GGNBP2 absence was also involved in regulation of kidney development and the reproductive system through bioinformatics analysis. The inheriting risk of 17q12 deletion syndrome is about 50%, and it is recommended to provide genetic counseling to all patients who are suspected or diagnosed with the syndrome.

BACKGROUND: Hepatocyte nuclear factor-1 beta (HNF1B) encodes a homeodomain-containing transcription factor, which is expressed early in embryogenesis and is involved in the development of multiple tissues and organs. HNF1B mutations cause complex multisystem disorders, with renal developmental disease and maturity onset diabetes of the young (HNF1B MODY), a rare cause of diabetes mellitus, being representative features.
METHODS: We present two adolescent boys from different socioeconomic backgrounds who were diagnosed with genetically confirmed HNF1B MODY following hospitalization for diabetic ketoacidosis in the first case and after diagnostic work-up due to impaired glucose tolerance in the second case. Multisystem manifestations, including pancreatic hypoplasia and early-onset diabetes mellitus (DM), renal cysts, hypomagnesemia, hyperuricemia, liver and biliary impairment, genital tract malformations, and primary hyperparathyroidism were also present, strongly suggesting HNF1B MODY.
RESULTS: The first patient was treated with subcutaneous insulin but was lost to follow-up due to social reasons. Conversely, early diagnosis in the second patient allowed the management of multisystem defects by a multidisciplinary team of experts. Moreover, manifestation of HNF1B MODY in the form of diabetic ketoacidosis was prevented and a structured diabetes training program has proven successful in regulating glycemic control, postponing the necessity for insulin treatment.
CONCLUSIONS: Early genetic work-up of patients with dysglycemia associated with a specific phenotype suggestive of HNF1B MODY is extremely important in the care of children and adolescents with diabetes since it ensures that early and optimal management is initiated, thereby preventing the onset of life-threatening diabetic ketoacidosis and other multisystem complications and/or comorbidities.

UNASSIGNED: To analyze the prenatal diagnosis, parental verification, and pregnancy outcomes of three fetuses with 17ql2 microdeletion syndrome.
UNASSIGNED: We retrospectively reviewed 46 singleton pregnancies with anomalies in the urinary system who underwent amniocentesis from Feb 2022 to October 2023 in the Prenatal Diagnosis Center of Lianyungang Maternal and Child Health Hospital. These fetuses were subjected to chromosomal microarray analysis (CMA) and/or trio whole-exome sequencing (Trio-WES). We specifically evaluated these cases\' prenatal renal ultrasound findings and clinical characteristics of the affected parents.
UNASSIGNED: Three fetuses were diagnosed as 17q12 microdeletions, and the detection rate was 6.5% in fetuses with anomalies in the urinary system (3/46). The heterogeneous deletions range from 1.494 to 1.66 Mb encompassing the complete hepatocyte nuclear factor 1 homeobox B (HNF1B) gene. Fetuses with 17q12 deletion exhibited varied renal phenotypes. Moreover, the clinical phenotypes of the affected parents differed greatly in the two cases (case 2 and case 3) in which the deletion was inherited. For case 3, the mother manifested classic symptoms of 17q12 deletion syndrome as well as unreported characteristics, such as very high myopia.
UNASSIGNED: Our findings demonstrate the necessity and significance of offering prenatal genetic testing when various renal anomalies are detected. In addition, our study broadens the phenotypic spectrum of 17q12 deletions. Most importantly, our findings may allow timely supportive genetic counseling and guidance for pregnancy in affected families, e.g., with the help of preimplantation genetic testing (PGT).

The orchestration of fetal kidney development involves the precise control of numerous genes, including HNF1A, HNF1B and PKHD1. Understanding the genetic factors influencing fetal kidney development is essential for unraveling the complexities of renal disorders. This study aimed to search for disease-causing variants in HNF1A, HNF1B, PKHD1 genes, among fetus and babies or via parental samples, using sanger sequencing, NGS technologie and MLPA. The study revealed an absence of gene deletions and disease-causing variants in the HNF1B gene. However, five previously SNPs in the HNF1A gene were identified in four patients (patients 1, 2, 3, and 4). These include c.51C > G (Exon1, p. Leu17=), c.79A > C (Exon1, p. Ile27Leu), c.1375C > T (Exon7, p. Leu459=), c.1460G > A (Exon7, p. Ser487Asn), and c.1501 + 7G > A (Intron7). Additionally, in addition to previously SNPs identified, a de novo heterozygous missense mutation (p.E508K) was detected in patient 4. Furthermore, a heterozygous mutation in exon 16 (p. Arg494*; c.1480C > T) was identified in both parents of patient 5, allowing predictions of fetal homozygosity. Bioinformatic analyses predicted the effects of the c.1522G > A mutation (p.E508K) on splicing processes, pre-mRNA structures, and protein instability and conformation. Similarly, the c.1480C > T mutation (p. Arg494*) was predicted to introduce a premature codon stop, leads to the production of a shorter protein with altered or impaired function. Identification of variants in the HNF1A and in PKHD1 genes provides valuable insights into the genetic landscape of renal abnormalities in affected patients. These findings underscore the heterogeneity of genetic variants contributing to renal disorders and emphasize the importance of genetic screening.

Hepatocyte nuclear factor 1B (HNF1B) encodes a transcription factor expressed in developing human kidney epithelia. Heterozygous HNF1B mutations are the commonest monogenic cause of dysplastic kidney malformations (DKMs). To understand their pathobiology, we generated heterozygous HNF1B mutant kidney organoids from CRISPR-Cas9 gene-edited human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) reprogrammed from a family with HNF1B-associated DKMs. Mutant organoids contained enlarged malformed tubules displaying deregulated cell turnover. Numerous genes implicated in Mendelian kidney tubulopathies were downregulated, and mutant tubules resisted the cyclic AMP (cAMP)-mediated dilatation seen in controls. Bulk and single-cell RNA sequencing (scRNA-seq) analyses indicated abnormal Wingless/Integrated (WNT), calcium, and glutamatergic pathways, the latter hitherto unstudied in developing kidneys. Glutamate ionotropic receptor kainate type subunit 3 (GRIK3) was upregulated in malformed mutant nephron tubules and prominent in HNF1B mutant fetal human dysplastic kidney epithelia. These results reveal morphological, molecular, and physiological roles for HNF1B in human kidney tubule differentiation and morphogenesis illuminating the developmental origin of mutant-HNF1B-causing kidney disease.

OBJECTIVE: We present prenatal diagnosis and perinatal findings of 17q12 microdeletion encompassing HNF1B in a fetus with bilateral hyperechogenic kidneys on fetal ultrasound and mild renal abnormality after birth, and a review of the literature.
METHODS: A 36-year-old, primigravid woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Simultaneous array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes showed a de novo 1.38-Mb 17q12 microdeletion encompassing LHX1 and HNF1B. The parents did not have such a microdeletion. Prenatal ultrasound showed bilateral hyperechogenic kidneys with normal corticomedullary (CM) differentiation. The parents elected to continue the pregnancy, and a grossly normal 3180-g male baby was delivered at 39 weeks of gestation. aCGH analysis on the cord blood DNA revealed arr [GRCh37 (hg19)] 17q12 (34,856,055-36,248,918) × 1.0 with a 1.393-Mb microdeletion encompassing the genes of MYO19, PIGW, GGNBP2, DHRS11, MRM1, LHX1, AATF, ACACA, TADA2A, DUSP14, SYNRG, DDX52 and HNF1B. When follow-up at age 2 years and 4 months, the renal ultrasound revealed bilateral increased renal echogenicity with normal CM differentiation and small left renal cysts. The blood test revealed BUN = 28 mg/dL (normal: 5-18 mg/dL) and creatinine = 0.5 mg/dL (normal: 0.2-0.4 mg/dL).
CONCLUSIONS: 17q12 microdeletion encompassing LHX1 and HNF1B at prenatal diagnosis may present variable clinical spectrum with bilateral hyperechogenic kidneys on fetal ultrasound and mild renal abnormality after birth. Prenatal diagnosis of fetal hyperechogenic kidneys should raise a suspicion of 17q12 microdeletion syndrome.

UNASSIGNED: Maturity-onset diabetes of the young type 5 (MODY5) is an uncommon, underrecognized condition that can be encountered in several clinical contexts. It is challenging to diagnose because it is considered rare and therefore overlooked in the differential diagnosis. Moreover, no typical clinical features or routine laboratory tests can immediately inform the diagnosis.
UNASSIGNED: We report a 28-year-old man who was once misdiagnosed with type 1 diabetes due to decreased islet function and recurrent diabetic ketosis or ketoacidosis. However, he had intermittent nausea, vomiting, abdominal distension, and abdominal pain 6 months prior. Further examinations revealed agenesis of the dorsal pancreas, complex renal cyst, kidney stone, prostate cyst, hypomagnesaemia, and delayed gastric emptying. Accordingly, whole-exon gene detection was performed, and a heterozygous deletion mutation was identified at [GRCh37 (hg19)] chr17:34842526-36347106 (1.5 Mb, including HNF1B gene). The patient was eventually diagnosed with 17q12 deletion syndrome with gastroparesis.
UNASSIGNED: We report a novel case of diabetes mellitus type MODY5 as a feature of 17q12 deletion syndrome caused by a new 17q12 deletion mutation, which will further broaden the genetic mutation spectrum of this condition. With the help of gene detection technology, these findings can assist endocrinologists in making the correct diagnosis of MODY5 or 17q12 deletion syndrome. Additionally, they can formulate an appropriate therapy and conduct genetic screening counseling for their family members to guide and optimize fertility.

BACKGROUND: Mutation of the gene encoding Hepatocyte Nuclear transcription Factor-1 Beta (HNF1B) causes a rare monogenetic subtype of Maturity-Onset Diabetes of the Young (MODY). HNF1B-related MODY results in the dysfunction of multiple organ systems. However, genetic analysis enables personalized medicine for patients and families.
OBJECTIVE: To understand the clinical characteristics and explore the gene mutations in Croatian patients.
METHODS: This was a retrospective observational study of individuals (and their relatives) who were, due to the clinical suspicion of MODY, referred to the Department of Laboratory Diagnostics at the University Hospital Centre Zagreb for genetic testing.
RESULTS: A total of 118 participants, 56% females, were screened. Seven patients (three females) from five families were identified to have HNF1B-related MODY. The median age at diagnosis was 31 (11-45) years, the median c-peptide was 0.8 (0.55-1.39) nmol/L, the median HbA1c was 9.1 (5.7-18.4)%, and the median BMI was 22.9 kg/m2 (17-24.6). Patients had a variety of clinical manifestations; kidney disease was not as frequent as liver lesions, neuropsychiatric symptoms, hyperlipidemia, hyperuricemia, and hypomagnesemia. We identified two new pathogenic mutations (c.1006C > G protein p.His336Asp on exon 4 and c.1373T > G p protein Val458Gly on exon 7).
CONCLUSIONS: In a study involving Croatian patients, new genetic (two previously unknown mutations) and clinical (diverse range of clinical presentations) aspects of HNF1B-related MODY were found.

UNASSIGNED: Beta-cell monogenic forms of diabetes are the area of diabetes care with the strongest support for precision medicine. We reviewed treatment of hyperglycemia in GCK-related hyperglycemia, HNF1A-HNF4A- and HNF1B-diabetes, Mitochondrial diabetes (MD) due to m.3243A>G variant, 6q24-transient neonatal diabetes (TND) and SLC19A2-diabetes.
UNASSIGNED: Systematic reviews with data from PubMed, MEDLINE and Embase were performed for the different subtypes. Individual and group level data was extracted for glycemic outcomes in individuals with genetically confirmed monogenic diabetes.
UNASSIGNED: 147 studies met inclusion criteria with only six experimental studies and the rest being single case reports or cohort studies. Most studies had moderate or serious risk of bias.For GCK-related hyperglycemia, six studies (N=35) showed no deterioration in HbA1c on discontinuing glucose lowering therapy. A randomized trial (n=18 per group) showed that sulfonylureas (SU) were more effective in HNF1A-diabetes than in type 2 diabetes, and cohort and case studies supported SU effectiveness in lowering HbA1c. Two crossover trials (n=15 and n=16) suggested glinides and GLP-1 receptor agonists might be used in place of SU. Evidence for HNF4A-diabetes was limited. While some patients with HNF1B-diabetes (n=301) and MD (n=250) were treated with oral agents, most were on insulin. There was some support for the use of oral agents after relapse in 6q24-TND, and for thiamine improving glycemic control and reducing insulin requirement in SLC19A2-diabetes (less than half achieved insulin-independency).
UNASSIGNED: There is limited evidence to guide the treatment in monogenic diabetes with most studies being non-randomized and small. The data supports: no treatment in GCK-related hyperglycemia; SU for HNF1A-diabetes. Further evidence is needed to examine the optimum treatment in monogenic subtypes.

Mutations in the hepatocyte nuclear factor-1-beta (HNF1B) gene cause a variety of diseases in different organ systems. Mutations have been described as causing neonatal cholestasis, maturity-onset diabetes of the young (type 5), cortical renal cysts, urogenital abnormalities, liver dysfunction, and atrophy of the pancreas. We describe a male patient who presented with cholestatic liver disease in infancy which progressed by age 14 to end-stage liver disease due to HNF1B disease. He subsequently underwent liver transplantation at age 15 and then developed diabetes requiring insulin which did not resolve after cessation of corticosteroids. To our knowledge, this is the first case reported of liver transplantation for decompensated cirrhosis secondary to HNF1B disease.