Genetic Disorders Research Articles

Exploring the Role of Genetic Testing in Decisions to Redirect Care in Critically Ill Infants.

Genetic disorders are a major determinant of morbidity and mortality within neonatal intensive care units (NICUs). Studies have found genetic testing in critically ill infants may lead to changes in clinical decisions such as pursuing end of life care. This study surveyed palliative care providers to explore the influence of genetic testing on decisions to redirect care in critically ill infants. This study was conducted retrospectively on cases who were admitted to the Level IV NICU at Primary Children's Hospital, underwent redirection to end of life care, and whose death date was between 2019-2023. A review of the case's electronic medical record was performed to construct a clinical case summary. The clinical summary and questionnaire were sent to the case's palliative care provider. Fifty-six cases were included in this study and 73% had genetic testing completed. Our results suggest the information from genetic testing played a relatively minor role in the decision to redirect care for cases with negative or uncertain genetic testing and positive genetic testing results, although the influence appeared higher in the latter group. Our results suggest the assumptions of several studies that genetic testing is responsible for changes in clinical management and cost savings, especially in cases of redirection of care may have been overestimated. Our results fill a critical gap in current literature and demonstrate the need for further investigation to clarify the direct role of genetic testing in clinical decisions in the NICU, especially related to redirection of care.

Motor phenotypes associated with genetic neurodevelopmental disorders.

There is a growing number of monogenic disorders implicated in neurodevelopmental disorders (NDDs), including autism spectrum disorder and intellectual disability. Motor impairment is frequently seen in these disorders, although not clearly defined. We aimed to characterize the motor phenotype of genetic NDDs. We analyzed data from Simons Searchlight, collecting information on patients with genetic NDDs. Data analyzed included Vineland Adaptive Behavior Scales Second Edition (Vineland-II) motor standard scores, motor milestones and tone abnormalities. In total, 959 patients with 57 genetic disorders were included. Disorders associated with Vineland-II motor standard score <56 included GRIN2B-related disorder (mean standard score = 53.5), HNRNPH2-related disorder (mean standard score = 55.8) and SCN2A-related disorder (mean standard score = 49.9). The only genetic condition with a mean age of sitting unsupported ≥18 months was GRIN1-related disorder (mean age = 26.3 months). Genetic conditions with a mean age of walking independently ≥36 months included CTNNB1-related disorder (mean age = 37.4 months) and HNRNPH2-related disorder (mean age = 41.9 months). Tone abnormalities included hypotonia in 83% (577/696), hypertonia in 16% (112/696), a diagnosis of cerebral palsy (CP) in 10% (73/696) and a diagnosis specifically of spastic CP in 3% (23/696). Patients with genetic NDDs have a spectrum of motor impairment, which warrant further characterization.

SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.

Intellectual disability is often the outcome of neurodevelopmental disorders and is characterized by significant impairments in intellectual and adaptive functioning. X-linked intellectual disability (XLID) is a subset of these disorders caused by genetic defects on the X chromosome, affecting about 2 out of 1,000 males. In syndromic form, it leads to a broad range of cognitive, behavioral, ocular, and physical disabilities. Employing exome or genome sequencing, here we identified 4 missense variants (c.475C > G; p.H159D, c.1373C > A; p.T458N, and c.1585G > A; p.E529K, c.953C > T; p.S318L) and a putative truncating variant (c.1413_1414del; p.Y471*) in the SRPK3 gene in 9 XLID patients from 5 unrelated families. To validate SRPK3 as a novel XLID gene, we established a knockout (KO) model of the SRPK3 orthologue in zebrafish. The 8 patients ascertained postnatally shared common clinical features including intellectual disability, agenesis of the corpus callosum, abnormal eye movement, and ataxia. A ninth case, ascertained prenatally, had a complex structural brain phenotype. Together, these data indicate a pathological role of SRPK3 in neurodevelopmental disorders. In post-fertilization day 5 larvae (free swimming stage), KO zebrafish exhibited severe deficits in eye movement and swim bladder inflation, mimicking uncontrolled ocular movement and physical clumsiness observed in human patients. In adult KO zebrafish, cerebellar agenesis and behavioral abnormalities were observed, recapitulating human phenotypes of cerebellar atrophy and intellectual disability. Overall, these results suggest a crucial role of SRPK3 in the pathogenesis of syndromic X-linked intellectual disability and provide new insights into brain development, cognitive and ocular dysfunction in both humans and zebrafish. ANN NEUROL 2024;96:914-931.

Thiamine: An indispensable regulator of paediatric neuro-cardiovascular health and diseases.

Physicians are recommended to have a low threshold for suspecting thiamine deficiency especially in vulnerable populations. Laboratory diagnosis of thiamine deficiency needs to be implemented as a standard of care, especially in endemic regions. Further, public health policies on food fortification, mandatory supplementation, and surveillance are imperative to eliminate thiamine deficiency-induced health hazards. • South Asian countries report a higher incidence of neonatal and under-five mortalities, many of which are attributed to maternal and perinatal micronutrient deficiencies. • Preventable causes of neonatal/ infantile deaths include birth factors (low birth weight, birth asphyxia), infectious diseases (pneumonia, diarrhoea, tetanus, tuberculosis, measles, diphtheria, malaria, acute infections), deficiency diseases and genetic diseases (vitamin & mineral deficiencies, IEMs, congenital heart disease, unexplained PPHN, SIDS etc). • Acute thiamine deficiency presenting as multisystemic syndromes, has unfortunately been a long standing unresolved public health concern. However, accessible surveillance and diagnostic strategies remain elusive in most clinical settings. • Despite decades of reports and emerging guidelines, diagnosis of thiamine deficiency is often missed and policy mandates at national level are yet to be implemented even in endemic countries. • This review provides a comprehensive summary of the biochemical role of thiamine, its key functions and effects on major organ systems, the diagnostic gap, the enigmatic presentation of acute thiamine deficiency, the plausible role of thiamine in other pathologies and the preventive measures at individual and community level.

Mechanisms of podocyte injury in genetic kidney disease.

Glomerular diseases are a leading cause of chronic kidney disease worldwide. Both acquired and hereditary glomerulopathies frequently share a common final disease mechanism: disruption of the glomerular filtration barrier, podocyte injury, and ultimately podocyte death and detachment. Over 70 monogenic causes of proteinuric kidney disease have been identified, and most of these genes are highly expressed in podocytes, regulating key processes such as maintenance of the slit diaphragm, regulation of actin cytoskeleton remodeling, and modulation of downstream transcriptional pathways. Collectively, these are increasingly being referred to as hereditary "podocytopathies," in which podocyte injury is the central feature driving proteinuria and kidney dysfunction. In this review, we provide an overview of the monogenic podocytopathies and discuss the molecular mechanisms by which single-gene defects lead to podocyte injury and ultimately glomerulosclerosis. We review how advances in genomic technology and a better understanding of the cell biological basis of disease have led to the development of more targeted and personalized therapeutic strategies, including an overview of small molecule and gene therapy approaches.

Exercise Alters FBF1-Regulated Novel-miRNA-1135 Associated with Hydrolethalus Syndrome 1 in Rheumatoid Arthritis: A Preliminary Study.

Hydrolethalus Syndrome 1 (HYDS1) is a rare disorder that occurs commonly in Finnish infants but originates from the mother. This autosomal recessive syn-drome is associated with the FBF1, which is usually expressed in the centriole. The FBF1 is an inheritable arthritis disease phenotype that includes rheumatoid arthritis. Several studies have investigated males with FBF1 mutation carriers also related to arthritis diseases, including those under rheumatoid arthritis conditions, which revealed the possibility of conferring the gene mutation to the next generation of offspring. Nonetheless, there are some complications of FBF1 mutation with target miRNAs that can be affected by exercise. The objective of this study was to evaluate the different exercises that can be utilized to suppress the FBF1 mutation targeted by Novel-rno-miRNAs-1135 as a biomarker and assess the effectiveness of exercise in mitigating the FBF1 mutation. Four exercise interventional groups were divided into exercise and non-exercise groups. One hundred microliter pristane-induced arthritis (PIA) was injected at the dorsal re-gion of the tails of rodents and introduced to the two PIA interventional groups. On day forty-five, all animals were euthanized, and total RNA was extracted from the blood samples of ro-dents, while polymerase chain reaction (PCR) was amplified by using 5-7 primers. Computeri-zation was used for miRNA regulation and analysis of target gene candidates. The novel-rno-miRNA-1135 was downregulated to FBF1 in exercise groups. The exercise was found to have no significant impact in terms of change in novel-rno-miRNA-1135 regulation of FBF1 expression. Exercise has no impact on novel-rno-miRNA-1135 targeted for FBF1 in autoso-mal recessive disease.

Granulomatous Colitis Due to Hermansky-Pudlak Syndrome

ABSTRACT Hermansky-Pudlak syndrome (HPS) is a rare genetic disorder characterized by oculocutaneous albinism, bleeding diathesis, and multiorgan involvement. Granulomatous enterocolitis may occur in a subset of patients. Distinguishing HPS from other diseases such as Crohn's disease can be challenging, and managing HPS-associated colitis is complex. Recent reports suggest potential efficacy of infliximab in treating HPS-related granulomatous colitis. Here, we document the case of a 27-year-old patient with genetically confirmed HPS type 1, presenting with granulomatous colitis and successfully treated with corticosteroids and infliximab.

Comprehensive phenotypic assessment of nonsense mutations in mitochondrial ND5 in mice.

Mitochondrial dysfunction induced by mitochondrial DNA (mtDNA) mutations has been implicated in various human diseases. A comprehensive analysis of mitochondrial genetic disorders requires suitable animal models for human disease studies. While gene knockout via premature stop codons is a powerful method for investigating the unique functions of target genes, achieving knockout of mtDNA has been rare. Here, we report the genotypes and phenotypes of heteroplasmic MT-ND5 gene-knockout mice. These mutant mice presented damaged mitochondrial cristae in the cerebral cortex, hippocampal atrophy, and asymmetry, leading to learning and memory abnormalities. Moreover, mutant mice are susceptible to obesity and thermogenetic disorders. We propose that these mtDNA gene-knockdown mice could serve as valuable animal models for studying the MT-ND5 gene and developing therapies for human mitochondrial disorders in the future.

Latent factors underlying the symptoms of adult-onset myotonic dystrophy type 1 during the clinical course

BackgroundMyotonic dystrophy type 1 (DM1) is a multisystem genetic disorder that classically presents with symptoms associated with myotonia, early onset cataracts, and muscular weakness, although the presentation and pattern of disease progression is quite varied. Presenting symptoms are well documented among adults with DM1. However, less is known about the co-occurrence of symptoms over time. We aimed to use factor analysis to explore the correlation pattern of signs and symptoms (S/S) that emerged during the clinical course.ResultsClinical records of 228 individuals with adult onset DM1 were abstracted using the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet) from a six-site cohort in the United States during an eight-year study period. Factor analysis was used to group the correlated S/S into latent factors. Three factors were identified. Group 1: ‘Facial Weakness/Myotonia’ includes the two most common S/S, as indicated by its name. Group 2: ‘Skeletal Muscle Weakness’ includes eight muscular S/S and is more frequently reported by males and those with older age at onset. Group 3: ‘Gastrointestinal distress/Sleepiness’ includes four non-muscular S/S and hand stiffness. The abstracted medical records reported that over 63% of individuals had S/S from all three groups. Associations of covariates with factor scores were also examined using linear regression. CTG repeat length was significantly positively associated with higher factor scores for all three factors.ConclusionsThis study identified three latent factors of S/S which accumulated during the clinical course of adult onset DM1.

The frontier of precision medicine: application of single-cell multi-omics in preimplantation genetic diagnosis.

The advent of single-cell multi-omics technologies has revolutionized the landscape of preimplantation genetic diagnosis (PGD), offering unprecedented insights into the genetic, transcriptomic, and proteomic profiles of individual cells in early-stage embryos. This breakthrough holds the promise of enhancing the accuracy, efficiency, and scope of PGD, thereby significantly improving outcomes in assisted reproductive technologies (ARTs) and genetic disease prevention. This review provides a comprehensive overview of the importance of PGD in the context of precision medicine and elucidates how single-cell multi-omics technologies have transformed this field. We begin with a brief history of PGD, highlighting its evolution and application in detecting genetic disorders and facilitating ART. Subsequently, we delve into the principles, methodologies, and applications of single-cell genomics, transcriptomics, and proteomics in PGD, emphasizing their role in improving diagnostic precision and efficiency. Furthermore, we review significant recent advances within this domain, including key experimental designs, findings, and their implications for PGD practices. The advantages and limitations of these studies are analyzed to assess their potential impact on the future development of PGD technologies. Looking forward, we discuss the emerging research directions and challenges, focusing on technological advancements, new application areas, and strategies to overcome existing limitations. In conclusion, this review underscores the pivotal role of single-cell multi-omics in PGD, highlighting its potential to drive the progress of precision medicine and personalized treatment strategies, thereby marking a new era in reproductive genetics and healthcare.

Transfer of mitochondrial DNA into the nuclear genome during induced DNA breaks

Mitochondria serve as the cellular powerhouse, and their distinct DNA makes them a prospective target for gene editing to treat genetic disorders. However, the impact of genome editing on mitochondrial DNA (mtDNA) stability remains a mystery. Our study reveals previously unknown risks of genome editing that both nuclear and mitochondrial editing cause discernible transfer of mitochondrial DNA segments into the nuclear genome in various cell types including human cell lines, primary T cells, and mouse embryos. Furthermore, drug-induced mitochondrial stresses and mtDNA breaks exacerbate this transfer of mtDNA into the nuclear genome. Notably, we observe that mitochondrial editors, including mitoTALEN and recently developed base editor DdCBE, can also enhance crosstalk between mtDNA and the nuclear genome. Moreover, we provide a practical solution by co-expressing TREX1 or TREX2 exonucleases during DdCBE editing. These findings imply genome instability of mitochondria during induced DNA breaks and explain the origins of mitochondrial-nuclear DNA segments.

Integrated mRNA-seq and miRNA-seq analysis reveals key transcription factors of HNF4α and KLF4 in ADPKD

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most prevalent genetic disorder affecting the kidneys. Understanding epigenetic regulatory mechanisms and the role of microRNAs (miRNAs) is crucial for developing therapeutic interventions. Two mRNA datasets (GSE7869 and GSE35831) and miRNA expression data (GSE133530) from ADPKD patients were used to find differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs), with a focus on genes regulated by hub transcription factors (TFs) and their target genes. The expression of hub TFs was validated in human kidneys and animal models through Western Blot (WB) and RT-PCR analysis. The location of the hub TF proteins in kidney cells was observed by a laser confocal microscope. A total of 2037 DEGs were identified. DEM analysis resulted in 59 up-regulated and 107 down-regulated miRNAs. Predicted target DEGs of DEMs indicated two top dysregulated TFs: hepatocyte nuclear factor 4 alpha (HNF4α) and Kruppel-like factor 4 (KLF4). RT-PCR, WB, and immunochemistry results showed that mRNA and protein levels of HNF4α were significantly decreased while KLF4 levels were significantly up-regulated in human ADPKD kidneys and Pkd1 conditional knockout mice compared with normal controls. Laser confocal microscopy revealed that KLF4 was mainly located in the cytoplasm while HNF4α was in the nucleus. Functional enrichment analysis indicated that genes regulated by HNF4α were mainly associated with metabolic pathways, while KLF4-regulated genes were linked to kidney development. Drug response prediction analysis revealed potential drug candidates for ADPKD treatment, including BI-2536, Sepantronium, and AZD5582. This integrated analysis provides new epigenetic insights into the complex miRNA-TF-mRNA network in ADPKD and identifies HNF4α and KLF4 as key TFs. These findings offer valuable resources for further research and potential drug development for ADPKD.

Imaging of Upper Tract Urothelial Carcinoma.

Upper tract urothelial carcinoma (UTUC) originates in the renal pelvis or ureters and typically affects elderly patients, with its incidence increasing over the past few decades. UTUC is a distinct clinical entity with more aggressive clinical behavior than that of lower tract urothelial carcinoma. Due to the significant challenge of acquiring an adequate tissue sample for biopsy, comprehensive risk stratification is required for treatment planning, including radical nephroureterectomy and kidney-sparing management. Imaging plays an important integrated role in risk assessment along with endoscopy and pathologic examination. Lifelong surveillance is required after treatment due to the high incidence of recurrent and metachronous tumors. Lynch syndrome is a frequently unrecognized genetic disorder associated with UTUC that warrants specific attention in patient management. UTUC may manifest with diverse imaging findings, including filling defects, wall thickening, and mass-forming lesions. CT urography is the preferred modality for diagnosis and staging or restaging of UTUC, with numerous technical variations. Efforts have been made to optimize image quality and radiation exposure. Due to its poor sensitivity for small lesions, use of MR urography is limited to special clinical scenarios (eg, when patients have contraindications to iodinated contrast agents). Fluorine 18 fluorodeoxyglucose PET helps to detect metastatic lesions. Image-guided biopsy may be considered for uncertain lesions. Radiologists need to be familiar with the imaging findings and their differential diagnoses. ©RSNA, 2024 Supplemental material is available for this article.

Comprehensive Exploration of CRISPR and Gene Editing Technologies: Applications, Ethical Considerations, and Future Implications in Genetic Research

CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) and other gene-editing technologies have revolutionized genetic research by enabling precise, targeted modifications of DNA sequences. This paper provides a comprehensive exploration of CRISPR technology, detailing its development, mechanism of action, and versatility in diverse applications. From advancements in medicine, including therapeutic interventions for genetic disorders, to innovations in agriculture aimed at enhancing crop resilience and yield, CRISPR's transformative potential is vast. However, the rapid evolution of gene editing presents significant ethical and societal challenges, particularly concerning human germline editing, ecological impacts, and issues of accessibility and equity. This paper examines these ethical considerations, emphasizing the need for robust regulatory frameworks and responsible scientific practices. It also projects the future trajectory of gene editing technologies, speculating on emerging trends, possible breakthroughs, and the global implications of CRISPR in fields such as personalized medicine, synthetic biology, and biotechnology. By critically analyzing current applications and addressing ethical concerns, this study aims to provide a balanced perspective on CRISPR's potential to reshape genetic research while advocating for ethical governance and public engagement in its ongoing development. CRISPR’s ability to target specific genes with high accuracy has made it an invaluable tool not only in research laboratories but also in clinical settings, where it shows promise in treating previously incurable diseases. Recent advancements have extended CRISPR’s applications beyond simple gene knockout, allowing for base editing, prime editing, and epigenetic modifications that expand the possibilities for genetic correction and enhancement. As scientists explore using CRISPR in complex organisms, the precision and control required for safe and effective treatments become a key focus, particularly in addressing off-target effects that could lead to unintended genetic consequences.

Metabolic activation of WHO-congeners PCB28, 52, and 101 by human CYP2A6: evidence from in vitro and in vivo experiments.

Despite extensive research on the metabolism of polychlorinated biphenyls (PCBs), knowledge gaps persist regarding their isoform-specific biotransformation pathways. This study aimed to elucidate the role of different cytochrome P450 enzymes in PCB metabolism, focusing on WHO-congeners 2,4,4'-trichlorobiphenyl (PCB28), 2,2',5,5'-tetrachlorobiphenyl (PCB52), and 2,2',4,5,5'-pentachlorobiphenyl (PCB101). Utilizing engineered HEK293 cell lines, we investigated the in vitro metabolism of these PCBs by CYP1A2, CYP2C8, CYP2C9, CYP3A4, CYP2A6, and CYP2E1, revealing robust production of hydroxylated metabolites. Our results show that CYP2A6 plays a major role in the metabolism of these congeners responsible for predominant formation of para-position hydroxylated metabolites, with concentrations reaching up to 1.61µg/L (5,89nM) for PCB28, 316.98µg/L (1,03µM) for PCB52, and 151.1µg/L (441nM) for PCB101 from a 20µM parent PCB concentration. Moreover, concentration-dependent cytotoxic and cytostatic effects induced by reactive intermediates of the PCB hydroxylation pathway were observed in HEK293CYP2A6 cells, for all three congeners tested. CYP2A6 was specifically capable of activating PCBs 28 and 101 to genotoxic metabolites which produced genetic defects which were propagated to subsequent generations, potentially contributing to carcinogenesis. In a clinical study examining CYP2A6 enzyme activity in formerly exposed individuals with elevated internal PCB levels, a participant with increased enzyme activity showed a direct association between the phenotypic activity of CYP2A6 and the metabolism of PCB28, confirming the role of CYP2A6 in the in vivo metabolism of PCB28 also in humans. These results altogether reinforce the concept that CYP2A6 plays a pivotal role in PCB congener metabolism and suggest its significance in human health, particularly in the metabolism of lower chlorinated, volatile PCB congeners.

The Future of Cystic Fibrosis Care: Exploring AI's Impact on Detection and Therapy

: Cystic Fibrosis (CF) is a fatal hereditary condition marked by thicker mucus production, which can cause problems with the digestive and respiratory systems. The quality of life and survival rates of CF patients can be improved by early identification and individualized therapy measures. With an emphasis on its applications in diagnosis and therapy, this paper investigates how Artificial Intelligence (AI) is transforming the management of Cystic Fibrosis (CF). AI-powered algorithms are revolutionizing CF diagnosis by utilizing huge genetic, clinical, and imaging data databases. In order to identify CF mutations quickly and precisely, machine learning methods evaluate genomic profiles. Furthermore, AI-driven imaging analysis helps to identify lung and gastrointestinal issues linked to cystic fibrosis early and allows for prompt treatment. Additionally, AI aids in individualized CF therapy by anticipating how patients will react to already available medications and enabling customized treatment regimens. Drug repurposing algorithms find prospective candidates from already-approved drugs, advancing treatment choices. Additionally, AI supports the optimization of pharmacological combinations, enhancing therapeutic results while minimizing side effects. AI also helps with patient stratification by connecting people with CF mutations to therapies that are best for their genetic profiles. Improved treatment effectiveness is promised by this tailored strategy. The transformational potential of artificial intelligence (AI) in the field of cystic fibrosis is highlighted in this review, from early identification to individualized medication, bringing hope for better patient outcomes, and eventually prolonging the lives of people with this difficult ailment.

Genetic testing and counseling for hypertrophic cardiomyopathy: An evidence-based practice resource oftheNational Society of Genetic Counselors.

Hypertrophic cardiomyopathy (HCM) is a common hereditary condition affecting approximately 1 in 500 adults. It is characterized by marked clinical heterogeneity with individuals experiencing minimal to no symptoms, while others may have more severe outcomes including heart failure and sudden cardiac death. Genetic testing for HCM is increasingly available due to advances in DNA sequencing technologies and reduced costs. While a diagnosis of HCM is a well-supported indication for genetic testing and genetic counseling, incorporation of genetic services into the clinical setting is often limited outside of expert centers. As genetic counseling and testing have become more accessible and convenient, optimal integration of genomic data into the clinical care of individuals with HCM should be instituted, including delivery via genetic counseling. Drawing on recommendations from recent disease guidelines and systematic evidence reviews, we highlight key recommendations for HCM genetic testing and counseling. This practice resource provides a comprehensive framework to guide healthcare providers in the process of genetic test selection, variant classification, and cascade testing for genetic evaluation of HCM.

AI-empowered visualization of nucleic acid testing.

The visualization of nucleic acid testing (NAT) results plays a critical role in diagnosing and monitoring infectious and genetic diseases. The review aims to review the current status of AI-based NAT result visualization. It systematically introduces commonly used AI-based methods and techniques for NAT, emphasizing the importance of result visualization for accessible, clear, and rapid interpretation. This highlights the importance of developing a NAT visualization platform that is user-friendly and efficient, setting a clear direction for future advancements in making nucleic acid testing more accessible and effective for everyday applications.. This review explores both the commonly used NAT methods and AI-based techniques for NAT result visualization. The focus then shifts to AI-based methodologies, such as color detection and result interpretation through AI algorithms. The article presents the advantages and disadvantages of these techniques, while also comparing the performance of various NAT platforms in different experimental contexts. Furthermore, it explores the role of AI in enhancing the accuracy, speed, and user accessibility of NAT results, highlighting visualization technologies adapted from other fields of experimentation. This review offers valuable insights for researchers and everyday users, aiming to develop effective visualization platforms for NAT, ultimately enhancing disease diagnosis and monitoring.

Deciphering the mystery of CHNG3

Congenital hypothyroidism (CH), characterized by insufficient thyroid hormone production due to abnormalities in the hypothalamic-pituitary-thyroid axis, is the most common congenital endocrine disorder. We previously conducted comprehensive genetic screening of 102 patients with permanent CH born in Kanagawa Prefecture, Japan and identified mutations in several genes in 19 CH patients, including defects in genes encoding dual oxidase 2, thyroglobulin, thyrotropin receptor, thyroid peroxidase, and paired-box 8. Despite these findings, approximately 80% of cases remain unexplained. CH pedigrees unexplained by known genetic forms of CH have been reported in the literature and registered as congenital hypothyroidism, nongoitrous, 3 (CHNG3; %609893) in Online Mendelian Inheritance in Man. We also identified a Japanese pedigree of CH that was compatible with CHNG3. However, the exact genetic cause of CHNG3 was not revealed by standard analysis methods such as exome sequencing and array comparative genomic hybridization. We therefore took a combined approach and analyzed a total of 11 undiagnosed CH pedigrees by whole genome sequencing to analyze a 3-Mb linkage region, and found a disease-causing variant affecting a TTTG microsatellite in a noncoding region on chromosome 15. Further analysis revealed that 13.9% of 989 Japanese CH patients had abnormalities involving the TTTG microsatellite, with a substantial proportion (41.5%) of familial CH cases carrying these mutations. Identification of the genetic cause of CHNG3 provides new insights into the pathogenesis of CH, and highlights the need for continued exploration of noncoding genomic regions in Mendelian disorders of unknown etiology.

The role of STK11/LKB1 in cancer biology: implications for ovarian tumorigenesis and progression

STK11 (serine-threonine kinase 11), also known as LKB1 (liver kinase B1) is a highly conserved master kinase that regulates cellular metabolism and polarity through a complex signaling network involving AMPK and 12 other AMPK-related kinases. Germline mutations in LKB1 have been causatively linked to Peutz-Jeghers Syndrome (PJS), an autosomal dominant hereditary disease with high cancer susceptibility. The identification of inactivating somatic mutations in LKB1 in different types of cancer further supports its tumor suppressive role. Deleterious mutations in LKB1 are frequently observed in patients with epithelial ovarian cancer. However, its inconsistent effects on tumorigenesis and cancer progression suggest that its functional impact is genetic context-dependent, requiring cooperation with other oncogenic lesions. In this review, we summarize the pleiotropic functions of LKB1 and how its altered activity in cancer cells is linked to oncogenic proliferation and growth, metastasis, metabolic reprogramming, genomic instability, and immune modulation. We also review the current mechanistic understandings of this master kinase as well as therapeutic implications with particular focus on the effects of LKB1 deficiency in ovarian cancer pathogenesis. Lastly, we discuss whether LKB1 deficiency can be exploited as an Achilles heel in ovarian cancer.