Maturity-onset diabetes of the young resulting from mutations of the NEUROD1 gene (NEUROD1-MODY) is a rare form of diabetes and has not been well studied. We aimed to estimate its prevalence in Chinese patients with early-onset type 2 diabetes mellitus (EOD) and summarize its clinical and genetic characteristics.

We performed next-generation sequencing in 679 patients with EOD to screen rare variants in NEUROD1 exons and evaluated the effects of variants using in vitro experiments. All the reported NEUROD1-MODY cases were reviewed. Patients carrying pathogenic or likely pathogenic variants were diagnosed with NEUROD1-MODY according to the American College of Medical Genetics and Genomics guidelines.

Four rare variants were identified in 679 patients with EOD, but only P197H decreased the transcriptional activity in in vitro functional assays to an extent comparable to the well-known mutation causing NEUROD1-MODY. Its frequency was pretty higher in the European population (0.024) than that in the East Asian population (0.00034) according to the gnomAD database. Twenty-eight previously reported patients could be confirmed as diagnosed. The patients in Asia had a lower body mass index and a higher rate of ketosis compared with Caucasians, and the mutations present in Asia often occurred in the transactivation domain. Neurological abnormalities were observed in 10.7% of the patients with NEUROD1-MODY.

NEUROD1-MODY in Chinese patients with EOD is not common (≤ 0.15%). The P197H might account for MODY in Chinese with a higher penetrance than Caucasian and needs further exploration. The possible differences of phenotypes exist between the two ethnic populations.

In recent years, there has been a considerable influx of publications assessing the penetrance of pathogenic variants associated with monogenic diseases with dominant inheritance. As large and diverse groups have been sequenced, it has become clear that incomplete penetrance is common to most hereditary diseases, as numerous molecular, genetic, or environmental factors can cause clinical diversity among the carriers of the same variant. In this review, we discuss some of these factors and focus on the existing approaches to estimating penetrance, depending on the data available and their application to different data sets. We also list some currently available large-scale data sets with penetrance estimates.

Loss-of-function genetic variants (LoFs) often result in severe phenotypes, including autosomal dominant diseases driven by haploinsufficiency. Due to low carrier frequencies, their penetrance is generally unknown but typically variable. Here, we investigate the penetrance of >6,000 predicted LoFs (pLoFs) linked to 91 haploinsufficient diseases using a cohort of ≈24,000 carriers with linked electronic health record data. We find evidence for widespread reduced penetrance, which persisted after accounting for variant annotation artifacts, missed diagnoses, and incomplete clinical data. We thus hypothesized that many pLoFs have incomplete penetrance, which may be driven by residual allelic activity. To test this, we trained machine learning models to predict pLoF penetrance using variant-specific genomic features that may correlate with incomplete loss-of-function. The models were predictive of pLoF penetrance across a range of diseases and variant types, including those with prior clinical evidence for pathogenicity. This suggests that many pLoFs have incomplete penetrance due to residual allelic activity, complicating disease prognostication in asymptomatic carriers.

This article is based on the address given by the author at the 2024 meeting of The American Society of Human Genetics (ASHG) in Denver, CO. A video of the original address can be found at the ASHG website.

Completion of the Human Genome Project prompted predictions that genomics would transform medicine, including through genomic screening that identifies potentially medically actionable findings that could prevent disease, detect it earlier, or treat it better. However, genomic screening remains anchored in research and largely unavailable as part of routine care.

To summarize 11 years of experience with genomic screening and explore the landscape of genomic screening efforts.

This cohort study was based in Geisinger's MyCode Community Health Initiative, a genomic screening program in a rural Pennsylvania health care system in which patient-participants exomes are analyzed.

Genomic screen-positive rates were evaluated and stratified by condition type (cancer, cardiovascular, other) and US Centers for Disease Control and Prevention (CDC) Tier 1 designation. The proportion of participants previously unaware of their genomic result was assessed. Other large-scale population-based genomic screening efforts with genomic results disclosure were compiled from public resources.

A total of 354 957 patients participated in Geisinger's genomic screening program (median [IQR] age, 54 [36-69] years; 194 037 [59.7%] assigned female sex at birth). As of June 2024, 175 500 participants had exome sequencing available for analysis, and 5934 participants (3.4%) had a pathogenic variant in 81 genes known to increase risk for disease. Between 2013 and July 2024, 5119 results were disclosed to 5052 eligible participants, with 2267 (44.2%) associated with risk for cardiovascular disease, 2031 (39.7%) with risk for cancer, and 821 (16.0%) with risk for other conditions. Most results (3040 [59.4%]) were in genes outside of those with a CDC Tier 1 designation. Nearly 90% of participants (4425 [87.6%]) were unaware of their genomic risk prior to disclosure. In a survey of large-scale biobanks with genomic and electronic health record (EHR) data, only 25.0% (6 of 24) disclosed potentially actionable genomic results.

In this large, genomics-informed cohort study from a single health system, 1 in 30 participants had a potentially actionable genomic finding. However, nearly 90% were unaware of their risk prior to screening, demonstrating the utility of genomic screening in identifying at-risk individuals. Most large-scale biobanks with genomic and EHR data did not return genomic results with potential medical relevance, missing opportunities to significantly improve genomic risk ascertainment for these individuals and to perform longitudinal studies of clinical and implementation outcomes in diverse settings.

Type 2 diabetes (T2D) etiology is highly complex due to its multiple roots of origin. Polygenic risk scores (PRS) based on genome-wide association studies (GWAS) can partially explain T2D risk. Asian Indian people have up to six times higher risk of developing T2D than European people, and underlying causes of this disparity are unknown.

We have performed targeted sequencing of ten T2D GWAS/candidate regions using endogamous Punjabi Sikh families and replication studies using unrelated Sikh people and families from three other Indian endogamous ethnic groups (EEGs).

We detect rare and ultra-rare variants (RVs) in KCNJ11-ABCC8 and HNF4A (MODY genes) cosegregated with late-onset T2D. We also identify RV enrichment in two new genes, SLC38A11 and ANPEP, associated with T2D. Gene-burden analysis reveals the highest RV burden contributed by HNF4A (p = 0.0003), followed by KCNJ11/ABCC8 (p = 0.0061) and SLC38A11 (p = 0.03). Some RVs detected in Sikh people are also found in Agarwals from Jaipur, both from Northern India, but were monomorphic in other two EEGs from South Indian people. Despite carrying a high burden of T2D and RVs, most families have a significantly lower burden of PRS. Functional studies show that an intronic regulatory variant (RV) in ABCC8 affects the binding of Pax4 and NF-kB transcription factors, influencing downstream gene regulation.

The high burden of T2D in these families may stem from the enrichment of noncoding RVs in a small number of major known genes (including MODY genes) with oligogenic inheritance alongside RVs from genes associated with polygenic susceptibility. These findings highlight the need to conduct deeper evaluations of families from non-European ancestries to identify potential novel therapeutics and implement preventative strategies.

Investigating the genetic factors influencing human birth weight may lead to biological insights into fetal growth and long-term health. We report analyses of rare variants that impact birth weight when carried by either fetus or mother, using whole exome sequencing data in up to 234,675 participants. Rare protein-truncating and deleterious missense variants are collapsed to perform gene burden tests. We identify 9 genes; 5 with fetal-only effects on birth weight, 1 with maternal-only effects, 3 with both, and observe directionally concordant associations in an independent sample. Four of the genes were previously implicated by GWAS of birth weight. IGF1R and PAPPA2 (fetal and maternal-acting) have known roles in insulin-like growth factor bioavailability and signalling. PPARG, INHBE and ACVR1C (fetal-acting) are involved in adipose tissue regulation, and the latter two also show associations with favourable adiposity patterns in adults. We highlight the dual role of PPARG (fetal-acting) in adipocyte differentiation and placental angiogenesis. NOS3 (fetal and maternal-acting), NRK (fetal), and ADAMTS8 (maternal-acting) have been implicated in placental function and hypertension. To conclude, our analysis of rare coding variants identifies regulators of fetal adipose tissue and fetoplacental angiogenesis as determinants of birth weight, and further evidence for the role of insulin-like growth factors.

To follow up results from an earlier study using an extended sample of 470,000 exome-sequenced subjects to identify genes associated with type 2 diabetes (T2D) and to characterise the distribution of rare variants in these genes.

Exome sequence data for 470,000 UK Biobank participants was analysed using a combined phenotype for T2D obtained from diagnostic and prescription data. Gene-wise weighted burden analysis of rare coding variants in the new cohort of 270,000 samples was carried out for the 32 genes previously significant with uncorrected p < 0.001 along with 7 other genes previously implicated in T2D. Follow-up studies of GCK, GIGYF1, HNF1A and HNF4A used the full sample of 470,000 to investigate the effects of different categories of variant.

No novel genes were identified as exome wide significant. Rare loss of function (LOF) variants in GCK exerted a very large effect on T2D risk but more common (though still very rare) nonsynonymous variants classified as probably damaging by PolyPhen on average approximately doubled risk. Rare variants in the other three genes also had large effects on risk.

In spite of the very large sample size, no novel genes are implicated. Coding variants with an identifiable effect are collectively too rare be generally useful for guiding treatment choices for most patients. The finding that some nonsynonymous variants in GCK affect T2D risk is novel but not unexpected and does not have obvious practical implications. This research has been conducted using the UK Biobank Resource.

Natural HbA1c levels in GCK Maturity-onset diabetes of the young (GCK-MODY) patients often sit above the diagnostic threshold for type 2 diabetes (T2D). Treatments to lower HbA1c levels show reduced effectiveness in these individuals, yet in case studies to date, GCK-MODY patients often evade secondary T2D complications. Given these deviations, genetic screening of GCK may be clinically useful, but population studies are needed to more broadly understand T2D-related complications in GCK variant carriers.

To identify GCK variant carriers at the population level, we used both ACMG/AMP variant interpretation for GCK-MODY pathogenicity and a state-of-the-art variant interpretation strategy based on functional and statistical evidence to predict glucose elevations. Presence of pathogenic and glucose-elevating GCK variants was assessed in two cohorts (n~535,000). We identified 442 individuals with GCK variants predicted to increase glucose (~1/1200), with 150 (34%) of these individuals harboring variants reaching a pathogenic interpretation.

In a retrospective analysis, we show that in addition to elevated HbA1c, pathogenic variant carriers are 10x as likely, and all other glucose-elevating GCK variant carriers are 3x as likely, to receive a T2D diagnosis compared to non-GCK carriers. Surprisingly, carriers of pathogenic and glucose-elevating GCK variants with T2D develop T2D-related complications at rates more than double that of individuals without T2D, comparable to non-GCK individuals with T2D.

This population-level assessment shows secondary complications in individuals with pathogenic and glucose-elevating GCK variants and T2D and suggests that genotyping for these variants should be considered in a precision medicine approach for T2D treatment and prevention.

Type 2 diabetes (T2D) genome-wide association studies (GWASs) often overlook rare variants as a result of previous imputation panels' limitations and scarce whole-genome sequencing (WGS) data. We used TOPMed imputation and WGS to conduct the largest T2D GWAS meta-analysis involving 51,256 cases of T2D and 370,487 controls, targeting variants with a minor allele frequency as low as 5 × 10-5. We identified 12 new variants, including a rare African/African American-enriched enhancer variant near the LEP gene (rs147287548), associated with fourfold increased T2D risk. We also identified a rare missense variant in HNF4A (p.Arg114Trp), associated with eightfold increased T2D risk, previously reported in maturity-onset diabetes of the young with reduced penetrance, but observed here in a T2D GWAS. We further leveraged these data to analyze 1,634 ClinVar variants in 22 genes related to monogenic diabetes, identifying two additional rare variants in HNF1A and GCK associated with fivefold and eightfold increased T2D risk, respectively, the effects of which were modified by the individual's polygenic risk score. For 21% of the variants with conflicting interpretations or uncertain significance in ClinVar, we provided support of being benign based on their lack of association with T2D. Our work provides a framework for using rare variant GWASs to identify large-effect variants and assess variant pathogenicity in monogenic diabetes genes.

Genomic ascertainment of electronic health record-linked exome data in two large biobanks was used to quantify germline pathogenic/likely pathogenic (P/LP) variant prevalence, cancer prevalence, and survival in adults with non-NF1 RAS/mitogen-activated protein kinase genes (RASopathies).

Germline RASopathy variants were examined from adult participants in UK Biobank (UKBB; n=469,802), Geisinger MyCode (n=167,050) and Mount Sinai BioMe (n=30,470). Variants were classified as per American College of Medical Genetics/Association for Molecular Pathology criteria and reviewed by a RASopathy variant expert. Heterozygotes harbored a RASopathy pathogenic/likely pathogenic variant; controls harbored wild type or benign/likely benign RASopathy variation. To distinguish germline variants from clonal hematopoiesis, benign tissues were Sanger sequenced. Tumor phenotype and demographic data were retrieved from MyCode and UKBB.

Pathogenic variants in Noonan syndrome-associated genes (excluding known Noonan syndrome with multiple lentigines variants) were the most common with an estimated prevalence that ranged between 1:1,772-1:3,330 in the three cohorts. Pathogenic variants in cardiofaciocutaneous syndrome-associated genes had an estimated prevalence of 1:41,762-1:55,683 in two cohorts. Pathogenic variants in SPRED1 (Legius syndrome) were more frequent in UKBB (1:19,567 [95%CI: 1:13,150-1:29,116]) compared to MyCode (1:41,762 [95%CI: 1:15,185-1:130,367]). In SPRED1-heterozygotes, cancer prevalence was significantly increased in UKBB (OR:3.8 [95% CI: 2.48-8.64]; p=1.2×10-3) but not in the MyCode cohort. Pathogenic variants in HRAS (Costello syndrome) were not identified. In MyCode and UKBB cohorts, there was no significant increase in cancer prevalence in individuals with Noonan-, CBL- and CFC syndrome-associated pathogenic variants.

Genomic ascertainment from two large biobanks did not show evidence of elevated cancer risk in adult Noonan syndrome heterozygotes. There may be an increased cancer risk for adult SPRED1 heterozygotes.

Penetrance is the probability that an individual with a pathogenic genetic variant develops a specific disease. Knowing the penetrance of variants for monogenic disorders is important for counseling of individuals. Until recently, estimates of penetrance have largely relied on affected individuals and their at-risk family members being clinically referred for genetic testing, a 'phenotype-first' approach. This approach substantially overestimates the penetrance of variants because of ascertainment bias. The recent availability of whole-genome sequencing data in individuals from very-large-scale population-based cohorts now allows 'genotype-first' estimates of penetrance for many conditions. Although this type of population-based study can underestimate penetrance owing to recruitment biases, it provides more accurate estimates of penetrance for secondary or incidental findings. Here, we provide guidance for the conduct of penetrance studies to ensure that robust genotypes and phenotypes are used to accurately estimate penetrance of variants and groups of similarly annotated variants from population-based studies.

BackgroundLynch syndrome (LS) is an inherited cancer predisposition syndrome caused by genetic variants affecting DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 Cancer risk in LS is estimated from cohorts of individuals ascertained by individual or family history of cancer, which may upwardly bias estimates.

830 carriers of pathogenic or likely pathogenic (path_MMR) MMR gene variants classified by InSiGHT were identified in 454 756 UK Biobank (UKB) participants using whole-exome sequence. Nelson-Aalen survival analysis was used to estimate cumulative incidence of colorectal, endometrial and breast cancer (BC).

Cumulative incidence of colorectal and endometrial cancer (EC) by age 70 years was elevated in path_MMR carriers compared with non-carriers (colorectal: 11.8% (95% confidence interval (CI): 9.5% to 14.6%) vs 1.7% (95% CI: 1.6% to 1.7%), endometrial: 13.4% (95% CI: 10.2% to 17.6%) vs 1.0% (95% CI: 0.9% to 1.0%)), but the magnitude of this increase differed between genes. Cumulative BC incidence by age 70 years was not elevated in path_MMR carriers compared with non-carriers (8.9% (95% CI: 6.3% to 12.4%) vs 7.5% (95% CI: 7.4% to 7.6%)). Cumulative cancer incidence estimates in UKB were similar to estimates from the Prospective Lynch Syndrome Database for all genes and cancers, except there was no evidence for elevated EC risk in carriers of pathogenic PMS2 variants in UKB.

These results support offering incidentally identified carriers of any path_MMR surveillance to manage colorectal cancer risk. Incidentally identified carriers of pathogenic variants in MLH1, MSH2 and MSH6 would also benefit from interventions to reduce EC risk. The results suggest that BC is not an LS-related cancer.

Maturity-onset diabetes of the young (MODY) is an uncommon monogenic type of diabetes mellitus. Detecting genetic variants for MODY is a necessity for precise diagnosis and treatment. The majority of MODY genetic predisposition has been documented in European populations and a lack of information is present in Iranians which leads to misdiagnosis as a consequence of defects in unknown variants. In this study, using genetic variant information of 20,002 participants from the family-based TCGS (Tehran Cardiometabolic Genetic Study) cohort, we evaluated the genetic spectrum of MODY in Iran. We concentrated on previously discovered MODY-causing genes. Genetic variants were evaluated for their pathogenicity. We discovered 6 variants that were previously reported in the ClinVar as pathogenic/likely pathogenic (P/LP) for MODY in 45 participants from 24 families (INS in 21 cases, GCK in 13, HNF1B in 8, HNF4A, HNF1A, and CEL in 1 case). One potential MODY variant with Uncertain Risk Allele in ClinVar classification was also identified, which showed complete disease penetrance (100%) in four subjects from one family. This is the first family-based study to define the genetic spectrum and estimate the prevalence of MODY in Iran. The discovered variants need to be investigated by additional studies.

Maturity-onset diabetes of the young (MODY) represents the most frequent form of monogenic diabetes mellitus (DM), currently classified in 14 distinct subtypes according to single gene mutations involved in the differentiation and function of pancreatic β-cells. A significant proportion of MODY has unknown etiology, suggesting that the genetic landscape is still to be explored. Recently, novel potentially MODY-causal genes, involved in the differentiation and function of β-cells, have been identified, such as RFX6, NKX2.2, NKX6.1, WFS1, PCBD1, MTOR, TBC1D4, CACNA1E, MNX1, AKT2, NEUROG3, EIF2AK3, GLIS3, HADH, and PTF1A. Genetic and clinical features of MODY variants remain highly heterogeneous, with no direct genotype-phenotype correlation, especially in the low-penetrant subtypes. This is a narrative review of the literature aimed at describing the current state-of-the-art of the novel likely MODY-associated variants. For a deeper understanding of MODY complexity, we also report some related controversies concerning the etiological role of some of the well-known pathological genes and MODY inheritance pattern, as well as the rare association of MODY with autoimmune diabetes. Due to the limited data available, the assessment of MODY-related genes pathogenicity remains challenging, especially in the setting of rare and low-penetrant subtypes. In consideration of the crucial importance of an accurate diagnosis, prognosis and management of MODY, more studies are warranted to further investigate its genetic landscape and the genotype-phenotype correlation, as well as the pathogenetic contribution of the nongenetic modifiers in this cohort of patients.

Our knowledge of X-linked Alport Syndrome [AS] comes mostly from selected cohorts with more severe disease.

We examined the phenotypic spectrum of X-linked AS in males and females with a genotype-based approach using data from the Geisinger MyCode DiscovEHR study, an unselected health system-based cohort with exome sequencing and electronic health records. Patients with COL4A5 variants reported as pathogenic (P) or likely pathogenic (LP) in ClinVar, or protein-truncating variants (PTVs), were each matched with up to 5 controls without COL4A3/4/5 variants by sociodemographics, diabetes diagnosis, and year of first outpatient encounter. AS-related phenotypes included dipstick hematuria, bilateral sensorineural hearing loss (BSHL), proteinuria, decreased eGFR, and ESKD.

Out of 170,856 patients, there were 29 hemizygous males (mean age 52.0 y [SD 20.0]) and 55 heterozygous females (mean age 59.3 y [SD 18.8]) with a COL4A5 P/LP variant, including 48 with the hypomorphic variant p.Gly624Asp. Overall, penetrance (having any AS phenotypic feature) was highest for non-p.Gly624Asp P/LP variants (males: 94%, females: 85%), intermediate for p.Gly624Asp (males: 77%, females: 69%), compared to controls (males: 32%; females: 50%). The proportion with ESKD was highest for males with P/LP variants (44%), intermediate for males with p.Gly624Asp (15%) and females with P/LP variants (10%), compared to controls (males: 3%, females 2%). Only 47% of individuals with COL4A5 had completed albuminuria screening, and a minority were taking renin-angiotensin aldosterone system (RAAS) inhibitors. Only 38% of males and 16% of females had a known diagnosis of Alport syndrome or thin basement membrane disease.

In an unselected cohort, we show increased risks of AS-related phenotypes in men and women compared to matched controls, while showing a wider spectrum of severity than has been described previously and variability by genotype. Future studies are needed to determine whether early genetic diagnosis can improve outcomes in Alport Syndrome.

Beta-cell monogenic forms of diabetes have strong support for precision medicine. We systematically analyzed evidence for precision treatments for GCK-related hyperglycemia, HNF1A-, HNF4A- and HNF1B-diabetes, and mitochondrial diabetes (MD) due to m.3243 A > G variant, 6q24-transient neonatal diabetes mellitus (TND) and SLC19A2-diabetes.

The search of PubMed, MEDLINE, and Embase for individual and group level data for glycemic outcomes using inclusion (English, original articles written after 1992) and exclusion (VUS, multiple diabetes types, absent/aggregated treatment effect measures) criteria. The risk of bias was assessed using NHLBI study-quality assessment tools. Data extracted from Covidence were summarized and presented as descriptive statistics in tables and text.

There are 146 studies included, with only six being experimental studies. For GCK-related hyperglycemia, the six studies (35 individuals) assessing therapy discontinuation show no HbA1c deterioration. A randomized trial (18 individuals per group) shows that sulfonylureas (SU) were more effective in HNF1A-diabetes than in type 2 diabetes. Cohort and case studies support SU's effectiveness in lowering HbA1c. Two cross-over trials (each with 15-16 individuals) suggest glinides and GLP-1 receptor agonists might be used in place of SU. Evidence for HNF4A-diabetes is limited. Most reported patients with HNF1B-diabetes (N = 293) and MD (N = 233) are on insulin without treatment studies. Limited data support oral agents after relapse in 6q24-TND and for thiamine improving glycemic control and reducing/eliminating insulin requirement in SLC19A2-diabetes.

There is limited evidence, and with moderate or serious risk of bias, to guide monogenic diabetes treatment. Further evidence is needed to examine the optimum treatment in monogenic subtypes.

Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease.

Women with maturity-onset diabetes of the young (MODY) need tailored antenatal care and monitoring of their offspring. Each MODY subtype has different implications for glycaemic targets, treatment choices and neonatal management. Hyperglycaemia of MODY is often first diagnosed in adolescence or early adulthood and therefore is clinically relevant to pregnant women. MODY remains an under-recognised and undiagnosed condition. Pregnancy represents an opportune time to make a genetic diagnosis of MODY and provide precision treatment. This review describes the nuance of antenatal care in women with MODY and the implications for pregnancies affected by a positive paternal genotype. Mutations in hepatic nuclear factor 1-alpha (HNF1A) and 4-alpha (HNF4A) genes are associated with progressive β-cell dysfunction resulting in early onset diabetes. Patients are largely managed with sulphonylureas outside of pregnancy. Macrosomia and persistent neonatal hypoglycaemia are reported in 54% and 15% of HNF4A genotype positive offspring respectively with a median increase in birthweight of 790 g. Close observation of foetal growth in utero allows optimal timing of delivery to minimise peri- and postpartum materno-foetal complications. Glucokinase (GCK)-MODY causes mild fasting hyperglycaemia which does not require treatment outside of pregnancy. Birthweight of offspring of maternal carriers is dependent on foetal genotype; heterozygous mutation carriers are usually normal weight while genotype negative offspring are large for gestational age (600 g heavier). Affected offspring of paternal carriers may be small for gestational age (500 g lighter). Serial growth scans with measurement of the abdominal circumference indirectly differentiate foetal genotype. Measurement of cell free foetal DNA in maternal blood from the late first trimester is superior to traditionally used ultrasound to distinguish foetal genotype. Cost and accessibility may limit its use.

Maturity-onset diabetes of the young (MODY) is part of the heterogeneous group of monogenic diabetes (MD) characterized by the non-immune dysfunction of pancreatic β-cells. The diagnosis of MODY still remains a challenge for clinicians, with many cases being misdiagnosed as type 1 or type 2 diabetes mellitus (T1DM/T2DM), and over 80% of cases remaining undiagnosed. With the introduction of modern technologies, important progress has been made in deciphering the molecular mechanisms and heterogeneous etiology of MD, including MODY. The aim of our study was to identify genetic variants associated with MODY in a group of patients with early-onset diabetes/prediabetes in whom a form of MD was clinically suspected. Genetic testing, based on next-generation sequencing (NGS) technology, was carried out either in a targeted manner, using gene panels for monogenic diabetes, or by analyzing the entire exome (whole-exome sequencing). GKC-MODY 2 was the most frequently detected variant, but rare forms of KCNJ11-MODY 13, specifically, HNF4A-MODY 1, were also identified. We have emphasized the importance of genetic testing for early diagnosis, MODY subtype differentiation, and genetic counseling. We presented the genotype-phenotype correlations, especially related to the clinical evolution and personalized therapy, also emphasizing the particularities of each patient in the family context.

Fanconi's syndrome (FS) is characterized by type-2 renal tubular acidosis, short stature, and renal rickets, along with glycosuria, aminoaciduria, hypophosphaturia, and urinary bicarbonate wasting. The genetic form of FS has been linked to HNF4A variants. Although additional clinical features such as hearing impairment have recently been associated with HNF4A-linked FS, its ocular manifestation has not been described.

Presenting a case of a 5-year-old male child with bilateral progressive corneal opacification and the presence of bilateral greyish-white deposits in the interpalpebral region since infancy. A next-generation sequencing (NGS)-based genetic testing was performed for the child followed by parental genetic testing for the identified variant. Furthermore, relevant works of literature were reviewed related to this condition.

Detailed corneal findings showed a bilateral band-shaped keratopathy (BSK) in the patient. Physical and systemic findings showed signs consistent with FS. Sequencing analysis revealed a novel heterozygous c.635C>T, (p.Pro212Leu) variant in the HNF4A gene in the proband and mother, while the father had a normal genotype.

Our case highlights the occurrence of BSK in an exceptionally rare manifestation of hereditary FS linked to HNF4A gene variant. The variant exists both in proband and asymptomatic mother. Therefore, the variable penetrance which is known to exist in HNF4A is acknowledged in this context. This report suggests the first documented instance establishing a plausible connection between BSK and HNF4A-associated FS, characterized by the variable penetrance attributed to the HNF4A gene.

Monogenic diabetes (MD) is caused by a mutation in a single gene and accounts for approximately 2.5-6% of all diabetes cases. Maturity-onset diabetes of the young (MODY) is the most common form of MD. To date, 14 different genes have been identified and associated with the presence of MODY phenotype. However, the number of potential candidate genes with relevance to beta cell function and glucose metabolism is increasing as more research is published. The aim of the study was to identify potentially causative variants in selected candidate genes in patients with a clinical diagnosis of MD.

Targeted Next-Generation Sequencing (tNGS) on Illumina NextSeq 550 platform involving Agilent SureSelectQXT Target Enrichment protocol for 994 patients with suspected MD was performed. In the next step, the sequencing data of 617 patients with no pathogenic variants in main MD-related genes were reanalysed for the presence of causative variants in six candidate genes (MTOR, TBC1D4, CACNA1E, MNX1, SLC19A2, KCNH6). The presence of the selected variants was confirmed by Sanger sequencing.

Seven heterozygous possibly damaging variants were identified in four candidate genes (MTOR, TBC1D4, CACNA1E, MNX1). Five changes were assessed as novel variants, not previously described in available databases. None of the described variants were present among patients previously diagnosed with MODY diabetes due to causative, pathogenic variants in known MODY-related genes.

The results obtained seem to confirm the effectiveness of the NGS method in identifying potentially causative variants in novel candidate genes associated with MODY diabetes.