A novel mutation in HNF1B promotes ferroptosis-mediated renal mesangial cells fibrosis.

Maturity onset diabetes of the young type 5(MODY5) is typically attributed to mutations in the HNF1B gene, which encodes transcription factors that play a significant role in kidney development and function maintenance. In this study, we identified a novel HNF1B gene mutation (c.445C > A) in a young male MODY5 patient exhibiting elevated serum creatinine levels and albuminuria. Through transfection of wild type and mutant HNF1B plasmids into mouse mesangial cells (MMCs), we investigated the impact on molecular indicators related to proliferation, fibrosis and oxidative stress. The results revealed that the HNF1B novel mutation promoted the expression of fibronectin, type 1 collagen, and CyclinD1, as well as increasing cellular oxidative stress and susceptibility to ferroptosis in MMCs. Our findings established a novel association between HNF1B mutant diseases and mesangial cell proliferation and fibrosis, suggesting that mutations of HNF1B may contribute to the progression of renal function in MODY5 patients. Additionally, our results implicate potential therapeutic targets for restraining fibrosis.

The Maturity-Onset Diabetes of the Young (MODY) Calculator Overestimates MODY Probability in Hispanic Youth.

CONTEXT: The applicability of the MODY risk calculator (Shields et al) to non- White European populations remains unknown. OBJECTIVE: We aimed to test its real-world application in Hispanic youth. METHODS: We conducted a retrospective chart review of Hispanic youth (<23 years) with diabetes (n=2033) in a large pediatric tertiary care center in the U.S. We calculated MODY probability for all subjects, splitting them into two cohorts based on the original model: Individuals who were started on insulin within 6 months of diabetes diagnosis (Cohort 1) and those who were not (Cohort 2). RESULTS: Cohort 1 consisted of 1566 individuals (median age [25p, 75p]: 16 [13, 19] years, 49% female), while Cohort 2 comprised 467 youth (median age [25p, 75p]: 17 [15, 20] years, 62% female). The mean MODY probability was 5.9% and 61.9% in Cohort 1 and Cohort 2, respectively. The mean probability for both cohorts combined was 18.8% suggesting an expected 382 individuals with MODY, which is much higher than previous estimations (1-5%; i.e. 20-102 individuals in this cohort). A total of 18 individuals tested positive for MODY among the limited number of individuals tested based on clinical suspicion and genetic testing availability (n=44 out of 2033 tested, [2.2% of overall cohort]). CONCLUSIONS: The MODY risk calculator likely overestimates the probability of MODY in Hispanic youth, largely driven by an overestimation in those not early-insulin treated (predominantly young-onset type 2 diabetes). The calculator needs updating to improve its applicability in this population. In addition, further research to help better identify MODY in Hispanic youth.

Treatment switch from multiple daily insulin injections to sulphonylureas in an African young adult diagnosed with HNF1A MODY: a case report.

BACKGROUND: Maturity onset diabetes of the young is one of the commonest causes of monogenic diabetes and can easily be mistaken for type 1 diabetes. A diagnosis of maturity onset diabetes of the young can have direct implications for genetic counseling, family screening, and precision diabetes treatment. However, the cost of genetic testing and identifying individuals to test are the main challenges for diagnosis and management in sub-Saharan Africa. We report the very first documented case of HNF1A maturity onset diabetes of the young in the sub-Saharan African region. CASE PRESENTATION: A 20-year-old female Black African young adult diagnosed with type 1 diabetes aged 14 presented for routine out-patient diabetes consultation. She was on multiple daily insulin injections; total combined dose 0.79 IU/kg/day with an HbA1c of 7.7%. The rest of her laboratory examinations were normal. On extended laboratory analysis, she had good residual insulin secretion with post-meal plasma C-peptide levels at 1150 pmol/L. She tested negative for glutamic acid decarboxylase (GAD65), islet antigen-2 (IA-2), and zinc transporter 8 (ZnT8) islet autoantibodies. Targeted next-generation sequencing (t-NGS) for monogenic diabetes was performed using DNA extracted from a buccal sample. She was diagnosed with HNF1A maturity onset diabetes of the young, with the c.607C > T; p.(Arg203Cys) pathogenic variant, which has never been reported in sub-Saharan Africa. Her clinical practitioners provided genetic and therapeutic counseling. Within 10 months following the diagnosis of maturity onset diabetes of the young, she was successfully switched from multiple daily insulin injections to oral antidiabetic tablets (sulphonylurea) while maintaining stable glycemic control (HBA1c of 7.0%) and reducing hypoglycemia. She expressed a huge relief from the daily finger pricks for blood glucose monitoring. CONCLUSION: This case reveals that HNF1A maturity onset diabetes of the young (and probably other causes of monogenic diabetes) can present in sub-Saharan Africa. A diagnosis of maturity onset diabetes of the young can have significant life-changing therapeutic implications.

Whole Exome Sequencing in Children With Type 1 Diabetes Before Age 6 Years Reveals Insights Into Disease Heterogeneity.

Aims: This study is aimed at comparing whole exome sequencing (WES) data with the clinical presentation in children with type 1 diabetes onset ≤ 5 years of age (EOT1D). Methods: WES was performed in 99 unrelated children with EOT1D with subsequent analysis to identify potentially deleterious rare variants in MODY genes. High-resolution HLA class II haplotyping, SNP genotyping, and T1D-genetic risk score (T1D-GRS) were also evaluated. Results: Eight of the ninety-nine EOT1D participants carried a potentially deleterious rare variant in a MODY gene. Rare variants affected five genes: GCK (n = 1), HNF1B (n = 2), HNF4A (n = 1), PDX1 (n = 2), and RFX6 (n = 2). At diagnosis, these children had a mean age of 3.0 years, a mean HbA1c of 10.5%, a detectable C-peptide in 5/8, and a positive islet autoantibody in 6/7. Children with MODY variants tend to exhibit a lower number of pancreatic autoantibodies and a lower fasting C-peptide compared to EOT1D without MODY rare variants. They also carried at least one high-risk DR3-DQ2 or DR4-DQ8 haplotype and exhibited a T1D-GRS similar to the other individuals in the EOT1D cohort, but higher than healthy controls. Conclusions: WES found potentially deleterious rare variants in MODY genes in 8.1% of EOT1D, occurring in the context of a T1D genetic background. Such genetic variants may contribute to disease precipitation by a ß-cell dysfunction mechanism. This supports the concept of different endotypes of T1D, and WES at T1D onset may be a prerequisite for the implementation of precision therapies in children with autoimmune diabetes.

Hidden MODY in Young Lean Women with Mild Glucose Intolerance Detected During Health Check-ups: Potential for Improved Pregnancy Outcomes Through Preconception Care.

Mild glucose intolerance (positive urine glucose or mild hyperglycemia) during health checkups in young, lean women may require specialist consultation. We herein report a 31-year-old Japanese woman with mild hyperglycemia detected during a checkup who was diagnosed with overt diabetes in pregnancy and HNF4A-MODY postpartum, without prior follow-up. This case highlights the following: MODY may be present in young, lean women with mild glucose intolerance, and preconception care may improve pregnancy outcomes. Fetal outcomes vary with MODY subtype. Preconception care is important.

Clinical screening for GCK-MODY in 2,989 patients from the Brazilian Monogenic Diabetes Study Group (BRASMOD) and the Brazilian Type 1 Diabetes Study Group (BrazDiab1SG).

Objectives: To evaluate the accuracy of routinely available parameters in screening for GCK maturity-onset diabetes of the young (MODY), leveraging data from two large cohorts - one of patients with GCK-MODY and the other of patients with type 1 diabetes (T1D). Materials and methods: The study included 2,687 patients with T1D, 202 patients with clinical features of MODY but without associated genetic variants (NoVar), and 100 patients with GCK-MODY (GCK). Area under the receiver-operating characteristic curve (ROC-AUC) analyses were used to assess the performance of each parameter - both alone and incorporated into regression models - in discriminating between groups. Results: The best parameter discriminating between GCK-MODY and T1D was a multivariable model comprising glycated hemoglobin (HbA1c), fasting plasma glucose, age at diagnosis, hypertension, microvascular complications, previous diabetic ketoacidosis, and family history of diabetes. This model had a ROC-AUC value of 0.980 (95% confidence interval [CI] 0.974-0.985) and positive (PPV) and negative (NPV) predictive values of 43.74% and 100%, respectively. The best model discriminating between GCK and NoVar included HbA1c, age at diagnosis, hypertension, and triglycerides and had a ROC-AUC value of 0.850 (95% CI 0.783-0.916), PPV of 88.36%, and NPV of 97.7%; however, this model was not significantly different from the others. A novel GCK variant was also described in one individual with MODY (7-44192948-T-C, p.Ser54Gly), which showed evidence of pathogenicity on in silico prediction tools. Conclusions: This study identified a highly accurate (98%) composite model for differentiating GCK-MODY and T1D. This model may help clinicians select patients for genetic evaluation of monogenic diabetes, enabling them to implement correct treatment without overusing limited resources.

Unraveling the genetic basis of MODY: insights from next-generation sequencing.

Maturity-onset diabetes of the young (MODY) is an uncommon kind of monogenic diabetes. The major characteristics of MODY include not having insulin resistance and the absence of autoimmunity, early onset, and a family history suggesting autosomal-dominant inheritance. Nonetheless, genetic testing is necessary for diagnosis. The MODY-related genes CEL, ABCC8, PDX1, GCK, WFS1, HNF4A, HNF1A, and HNF1B were examined using Next Generation Sequencing (NGS) in this investigation. This study aimed to evaluate the genetic and clinical characteristics of patients referred with a preliminary diagnosis of MODY, retrospectively. A total of 30 patients (18 male and 12 female) participated, with ages ranging from 5 to 56. Eight distinct genetic variants were identified in 17 cases (57%). Pathogenic variants in the HNF1A gene have been identified. Likely pathogenic variants were found in CEL, ABCC8, GCK, and HNF4A. The genes APPL1, BLK, INS, KCNJ1, KLF11, NEUROD1, PAX4, RFX6, and ZFP57 were shown to be mutation-free. Four distinct pathogenic variants are found in this series. Unexpectedly high rates of pathogenic variants have been found in the HNF1A gene. In 27% of cases, there is a family history of vertically transmitted diabetes. The study highlights the importance of genetic testing for individuals with early-onset diabetes and a strong family history of the condition. Comprehensive genetic testing and increased public awareness are essential for MODY.

Monogenic Defects of Beta Cell Function: From Clinical Suspicion to Genetic Diagnosis and Management of Rare Types of Diabetes.

Monogenic defects of beta cell function refer to a group of rare disorders that are characterized by early-onset diabetes mellitus due to a single gene mutation affecting insulin secretion. It accounts for up to 5% of all pediatric diabetes cases and includes transient or permanent neonatal diabetes, maturity-onset diabetes of the young (MODY), and various syndromes associated with diabetes. Causative mutations have been identified in genes regulating the development or function of the pancreatic beta cells responsible for normal insulin production and/or release. To date, more than 40 monogenic diabetes subtypes have been described, with those caused by mutations in HNF1A and GCK genes being the most prevalent. Despite being caused by a single gene mutation, each type of monogenic diabetes, especially MODY, can appear with various clinical phenotypes, even among members of the same family. This clinical heterogeneity, its rarity, and the fact that it shares some features with more common types of diabetes, can make the clinical diagnosis of monogenic diabetes rather challenging. Indeed, several cases of MODY or syndromic diabetes are accurately diagnosed in adulthood, after having been mislabeled as type 1 or type 2 diabetes. The recent widespread use of more reliable sequencing techniques has improved monogenic diabetes diagnosis, which is important to guide appropriate treatment and genetic counselling. The current review aims to summarize the latest knowledge on the clinical presentation, genetic confirmation, and therapeutic approach of the various forms of monogenic defects of beta cell function, using three imaginary clinical scenarios and highlighting clinical and laboratory features that can guide the clinician in reaching the correct diagnosis.

Course of pregnancy and 10-year observation of twins diagnosed with GCK-MODY in the neonatal period: a case report.

Monogenic diabetes accounts for 5% of all incidence of hyperglycemia and Maturity Onset Diabetes of the Young (MODY) is the most common form. In GCK-MODY, one of the most common forms of MODY, hyperglycemia is caused by a mutation of a gene responsible for coding glucokinase. At the clinical level, this condition presents as persistent, moderate and asymptomatic elevated fasting glucose levels and has a relatively low incidence of micro and macro-vascular complications. In general, the treatment of choice is to follow and maintain a healthy lifestyle. The incidence of GCK-MODY during pregnancy is 2% on average (0-6%). In this report, we introduce a case of a woman diagnosed with GCK-MODY during the pregnancy with twins, a boy and a girl, diagnosed with GCK-MODY after birth. We discuss the course of pregnancy, the need for access to fast and uncomplicated genetic diagnostics in utero, and the impact of the MODY diagnosis on the life of the mother and that of her children. In our case, the diagnosis of GCK-MODY was associated with a feeling of relief, after years of uncertainty, and helped to introduce more appropriate eating behaviors and lifestyle changes for both the mother and her children.

Comparison of Variants of Uncertain Significance in Three Regions of the Human Glucokinase Protein Using In Vitro and In Silico Analyses.

There is a growing field of research focusing on the bioinformatic analysis of human genetic variation and the associated diseases. To study how well in vitro testing of purified proteins compares to bioinformatic variant prediction, we chose to analyze glucokinase (GCK) missense variations between residues 119-132, 257-262, and 412-427. These regions contained a large number of variants of uncertain significance (VUS) as well as a few pathogenic variants to use for comparison. We compared experimentally produced Vmax values from purified GCK variant proteins to predictive methods such as molecular dynamics simulation, ConSurf, iStable, the evolutionary model of variant effect (EVE), PredictSNP, and calculated binding energy. After determining which variants are pathogenic or benign based on experimental results or previous genetic studies, we found that ConSurf was the best at predicting pathogenicity. Interestingly, one VUS, D262N, showed an increase in activity and thus was difficult to interpret as pathogenic or benign. This study is an attempt to provide a framework for the utility of missense variant predictive programs.

Expanded phenotypic spectrum in MODY 5 patients with 17q12 deletion syndrome: experience from an Indian tertiary care hospital.

OBJECTIVES: To study the clinical and genotypic spectrum of patients with HNF-1ß deletions (MODY 5) at a tertiary care hospital. METHODS: This study included four patients from the Department of Endocrinology at Sher-i-Kashmir Institute of Medical Sciences Srinagar with a strong clinical suspicion of MODY 5. Genetic analysis, including a monogenic gene panel comprising 78 genes associated with MODY and other similar forms of monogenic diabetes, was done. Dosage analysis of HNF 1B by Multiplex Ligand-dependent Probe Amplification (MLPA) was performed. RESULTS: The mean age of patients was 22.25 years with a male-to-female ratio of 3:1. Associated phenotypic features included neurodevelopmental disorder in all four patients, insulin resistance in two patients (2/4) and alopecia in three patients (3/4). One patient had clinical and biochemical hyperandrogenism. All patients had renal malformations, and one patient had a Mullerian anomaly. Family history was present in 1 patient. All patients had pancreatic abnormalities, the most common type being dorsal agenesis of the pancreas (3/4), followed by annular pancreas (1/4). All patients had a genetic deletion of the gene HNF1B on chromosome 17 with a deletion interval of (?_37686431)_(37745059_?), (?_37687281)-(37744884_?), comprising exons 1 to 9. CONCLUSIONS: It is imperative to maintain a high index of suspicion for MODY 5 in patients presenting with renal anomalies and diabetes, even in the absence of a family history. Early identification allows for screening family members and ensures a comprehensive approach to identifying and managing other abnormalities in these patients.

Modelling human diabetes ex vivo: a glance at maturity onset diabetes of the young.

Diabetes is a complex metabolic disease which most commonly has a polygenic origin; however, in rare cases, diabetes may be monogenic. This is indeed the case in both Maturity Onset Diabetes of the Young (MODY) and neonatal diabetes. These disease subtypes are believed to be simpler than Type 1 (T1D) and Type 2 Diabetes (T2D), which allows for more precise modelling. During the three last decades, many studies have focused on rodent models. These investigations provided a wealth of knowledge on both pancreas development and beta cell function. In particular, they allowed the establishment of a hierarchy of the transcription factors and highlighted the role of microenvironmental factors in the control of progenitor cell proliferation and differentiation. Transgenic mice also offered the possibility to decipher the mechanisms that define the functional identity of the pancreatic beta cells. Despite such interest in transgenic mice, recent data have also indicated that important differences exist between mice and human. To overcome these limitations, new human models are necessary. In the present review, we describe these ex vivo models, which are created using stem cells and organoids, and represent an important step toward islet cell therapy and drug discovery.

Co-inheritance of Rare Variants of Maturity-Onset Diabetes of the Young (MODY): A Case Report and Review of the Literature.

Maturity onset diabetes of the young (MODY) is a rare, monogenic autosomal dominant form of diabetes that is characterized by early-onset, non-insulin-dependent hyperglycemia, strong family history, and is often misdiagnosed as type 1 or type 2 diabetes. Co-inheritance of multiple MODY genes, however, is rare. We describe here a case of MODY involving co-inherited rare variants in the ABCC8 and B-lymphocyte kinase (BLK) genes. A 55-year-old non-obese man with a past medical history of dyslipidemia and premature ischemic heart disease was initially misdiagnosed with type 2 diabetes for more than 18 years. He is a smoker with a strong family history of diabetes affecting both of his parents and most of his siblings. Despite treatment with different oral antihyperglycemics, his diabetes remained uncontrolled with glycated hemoglobin (HBA1c) between 8 and 10% until the addition of gliclazide, which improved his HBA1c to 5.7%. Based on all the previous information, MODY was suspected, and genetic testing was done, which showed rare variants in the BLK and ABCC8 genes and suggested a co-occurrence of MODY11 and MODY12. This case highlights the importance of accurate genetic testing, which is crucial for proper MODY subtyping, enabling tailored treatment strategies and potentially improving patient outcomes. Moreover, the consistent presence of the BLK gene variant in limited cases of co-inheritance raises questions about its causative role in MODY, suggesting a need for further investigation into its clinical significance.

Monogenic diabetes.

Diseases in which genetic factors contribute to nearly 100% of the causation by single-gene mutations are referred to as monogenic disorders or Mendelian genetic diseases. These include neonatal diabetes mellitus (NDM), presenting within the first six months of life, maturity-onset diabetes of the young (MODY), developing later in childhood or adolescence, mitochondrial diabetes (MIDD), and insulin-resistant disorders, etc. On the other hand, common lifestyle-related diseases such as type 2 diabetes (T2DM), hypertension and dyslipidemia are multifactorial, emerging through complex interplay of genetic and environmental factors. The identification of causative genes for diabetes resulting from single-gene abnormalities not only unveils previously unknown mechanisms of insulin secretion and sensitivity at the molecular level but also reveals novel targets for drug development. Moreover, monogenic diabetes in which insulin secretion is impaired serve to clarify the pathophysiology and suggest therapeutic targets for the common multifactorial type 2 diabetes mellitus prevalent in the Japanese population, which is characterized by impaired insulin secretion. In this study, we characterize the various monogenic subtypes of diabetes so far identified.

Feasibility of a 12 weeks supervised exercise training intervention among people with Maturity Onset Diabetes of the Young (MODY) or type 2 diabetes in Greenland.

Preventing and managing Type 2 diabetes (T2D) involves adopting healthy lifestyle habits such as balanced nutrition and regular exercise. Maturity Onset Diabetes of The Young (MODY) shares diagnostic characteristics with T2D, but exercise responses in MODY remain unclear. In Greenland, MODY is 4-5 times more common than in other countries. No established exercise regimen exists for either T2D or MODY in Greenland. This study assessed the feasibility of a 12-week supervised exercise programme for MODY and T2D in Greenland, focusing on attendance, satisfaction, and effects on cardiovascular disease (CVD) risk factors and quality of life (QoL). Conducted as an experimental, two-armed, controlled trial, nine participants (4 with MODY) engaged in prescribed training sessions twice weekly for 45-60 minutes, while another nine (4 with MODY) formed the control group. Key outcomes included adherence rates, satisfaction levels, changes in HbA1c, body composition, aerobic fitness, blood pressure, CVD risk factors, and SF-12 scores. Although training adherence was modest at 56%, participant satisfaction remained high. Notable findings included a slight decrease of -0.3 mmol/l in HDL-cholesterol and a 5.7-point increase in the mental component (MCS) of SF-12 within the intervention group. However, the study underscores the need to refine the study design before supervised exercise programmes can be widely implemented in clinical settings in Greenland.

Pancreatic agenesis and altered m6A methylation in the pancreas of PDX1-mutant cynomolgus macaques.

As an essential transcriptional activator, PDX1 plays a crucial role in pancreatic development and ß-cell function. Mutations in the PDX1 gene may lead to type 4 maturity-onset diabetes of the young (MODY4) and neonatal diabetes mellitus. However, the precise mechanisms underlying MODY4 remain elusive due to the paucity of clinical samples and pronounced differences in pancreatic architecture and genomic composition between humans and existing animal models. In this study, three PDX1-mutant cynomolgus macaques were generated using CRISPR/Cas9 technology, all of which succumbed shortly postpartum, exhibiting pancreatic agenesis. Notably, one tri-allelic PDX1-mutant cynomolgus macaque (designated as M4) developed a pancreas, whereas the two mono-allelic PDX1-mutant cynomolgus macaques displayed no anatomical evidence of pancreatic formation. RNA sequencing of the M4 pancreas revealed substantial molecular changes in both endocrine and exocrine functions, indicating developmental delay and PDX1 haploinsufficiency. A marked change in m6A methylation was identified in the M4 pancreas, confirmed through cultured PDX1-mutant islet organoids. Notably, overexpression of the m6A modulator METTL3 restored function in heterozygous PDX1-mutant islet organoids. This study highlights a novel role of m6A methylation modification in the progression of MODY4 and provides valuable molecular insights for preclinical research.

[Striking manifestation and unexpected therapeutic course of diabetes mellitus in a 22-year-old male patient]. / Eindrucksvolle Manifestation und unerwarteter Therapieverlauf eines Diabetes mellitus bei einem 22-jährigen Patienten.

The case of a 22-year-old male patient who presented with acute on chronic hyperglycemia in known MODY ("maturity onset diabetes of the young") 12 (ABCC8 gene) after 11 months of treatment cessation is reported. To emphasize the importance of the awareness of this therapeutically important entity of diabetes, the essential facts of this inherited disease are summarized.

MODY calculator applied in patients with clinical diagnosis of type 1 diabetes mellitus: Is a higher cutoff needed?

Aim: This study aimed to evaluate the mean post-test probability (PTP) of the Maturity-onset diabetes of the young (MODY) calculator in a multiethnic cohort of patients previously diagnosed with type 1 diabetes (T1DM). Materials and methods: The MODY probability calculator proposed by Shields and colleagues (2012) was applied to 117 patients from a T1DM outpatient clinic at a tertiary hospital in Brazil. Additionally, two exons of the HNF1A gene were sequenced in eight patients who hadn't received insulin treatment within six months after the diagnosis. Results: 17.1 % of patients achieved PTP >10 %; 11.1 % achieved PTP >25 % (and all patients >30 %), and 7.7 % achieved PTP >40 %. Among the patients who were selected for genetic sequencing, 100 % presented PTP >30 %, with 66.6 % achieving PTP >40 % and 41.6 % achieving PTP >75 %. These cutoffs are as suggested for the Brazilian population, according to previous investigations. No mutation was observed in the sequenced exons. Conclusion: Considering that only around 10 % of the evaluated cases achieved PTP >30 %, it is highly probable that the most suitable cutoff to select patients for genetic sequencing in a Brazilian cohort of T1DM is higher than the cutoff used in Caucasian populations.

HNF1ß, LHX1, and GGNBP2 deletion contributed to kidney and reproductive dysfunction in 17q12 deletion syndrome: evidence from a case report.

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.