Identification of novel candidate predisposing genes in familial nonmedullary thyroid carcinoma implicating DNA damage repair pathways.

The genetic basis of nonsyndromic familial nonmedullary thyroid carcinoma (FNMTC) is still poorly understood, as the susceptibility genes identified so far only account for a small percentage of the genetic burden. Recently, germline mutations in DNA repair-related genes have been reported in cases with thyroid cancer. In order to clarify the genetic basis of FNMTC, 94 genes involved in hereditary cancer predisposition, including DNA repair genes, were analyzed in 48 probands from FNMTC families, through targeted next-generation sequencing (NGS). Genetic variants were selected upon bioinformatics analysis and in silico studies. Structural modeling and network analysis were also performed. In silico results of NGS data unveiled likely pathogenic germline variants in 15 families with FNMTC, in genes encoding proteins involved in DNA repair (ATM, CHEK2, ERCC2, BRCA2, ERCC4, FANCA, FANCD2, FANCF, and PALB2) and in the DICER1, FLCN, PTCH1, BUB1B, and RHBDF2 genes. Structural modeling predicted that most missense variants resulted in the disruption of networks of interactions between residues, with implications for local secondary and tertiary structure elements. Functional annotation and network analyses showed that the involved DNA repair proteins functionally interact with each other, within the same DNA repair pathway and across different pathways. MAPK activation was a common event in tumor progression. This study supports that rare germline variants in DNA repair genes may be accountable for FNMTC susceptibility, with potential future utility in patients' clinical management, and reinforces the relevance of DICER1 in disease etiology.

A Homozygous Variant in NAA60 Is Associated with Primary Familial Brain Calcification.

BACKGROUND: Primary familial brain calcification (PFBC) is a monogenic disorder characterized by bilateral calcifications in the brain. The genetic basis remains unknown in over half of the PFBC patients, indicating the existence of additional novel causative genes. NAA60 was a recently reported novel causative gene for PFBC. OBJECTIVE: The aim was to identify the probable novel causative gene in an autosomal recessive inherited PFBC family. METHODS: We performed a comprehensive genetic study on a consanguineous Chinese family with 3 siblings diagnosed with PFBC. We evaluated the effect of the variant in a probable novel causative gene on the protein level using Western blot, immunofluorescence, and coimmunoprecipitation. Possible downstream pathogenic mechanisms were further explored in gene knockout (KO) cell lines and animal models. RESULTS: We identified a PFBC co-segregated homozygous variant of c.460_461del (p.D154Lfs*113) in NAA60. Functional assays showed that this variant disrupts NAA60 protein localization to Golgi and accelerated protein degradation. The mutant NAA60 protein alters its interaction with the PFBC-related proteins PiT2 and XPR1, affecting intracellular phosphate homeostasis. Further mass spectrometry analysis in NAA60 KO cell lines revealed decreased expression of multiple brain calcification-associated proteins, including reduced folate carrier (RFC), a folate metabolism-related protein. CONCLUSIONS: Our study replicated the identification of NAA60 as a novel causative gene for autosomal recessive PFBC, demonstrating our causative variant leads to NAA60 loss of function. The NAA60 loss of function disrupts not only PFBC-related proteins (eg, PiT2 and XPR1) but also a wide range of other brain calcification-associated membrane protein substrates (eg, RFC), and provided a novel probable pathogenic mechanism for PFBC. © 2024 International Parkinson and Movement Disorder Society.

Heterozygous MEFV Mutation Leading to Renal Failure: A Case Study.

Familial Mediterranean fever (FMF) is an autosomal recessive disorder, particularly common in the Mediterranean area. Mutations in the MEVF gene cause it. AA Amyloidosis is the most severe complication of FMF leading to chronic renal failure. We describe a rare pediatric case of a phenotype I familial Mediterranean fever with V726A heterozygous mutation. The diagnosis was made at chronic kidney disease. We discuss through this case the importance of the early diagnosis of FMF heterozygous children which is not usually evident in some phenotypes. It will surely avoid fatal complications, inappropriate therapeutic approaches and higher healthcare costs.

Desmoplastic fibroma of the mandible in a 5-year-old child as an early oral manifestation of familial adenomatous polyposis.

Desmoplastic fibroma (DF) is a benign yet locally aggressive intraosseous tumour rarely encountered in the mandible. It often mimics other oral lesions. Familial adenomatous polyposis (FAP) is a condition in which individuals tend to develop multiple colorectal polyps, which may convert to colorectal cancer unless treated. FAP has various colonic and extra-colonic manifestations, including oral manifestations. A case of DF of the mandible in a 5-year-old child is presented here. The patient remained free of recurrence 4 years after segmental resection and immediate reconstruction with a fibula free flap. Subsequent genetic testing revealed FAP, implicating DF as an early oral manifestation. A review of the existing literature emphasizes the challenges in diagnosing DF and its association with FAP, stressing the importance of comprehensive assessment and genetic screening in suspected cases.

Prompt Cytopathological Diagnosis of Multiple Xanthomatous Skin Nodules in an Adolescent Girl Opening the Doors to Detection of Familial Hypercholesterolemia.

BACKGROUND: Xanthomas are papulo-nodular, yellow, soft, painless, dermal-based non-neoplastic cutaneous lesions that comprise of localized aggregates of lipid-laden histiocytes. CASE REPORT: A thirteen-year-old adolescent girl presented with multiple, large, bilateral, nodules present over elbows, posterior aspect of heel, and knees for five years. Fine needle aspiration cytology was performed, and the smears showed numerous foamy histiocytes, a few benign spindle cells, and foreign-body giant cells against a lipidaceous background. Her maternal aunt and grandmother also had xanthelasma palpebrarum. Serum lipid levels were advised and were markedly deranged in all three of them. Based on the corroborative clinical, biochemical, and cytopathological findings, a final diagnosis of familial hypercholesterolemia (FH) was rendered. CONCLUSION: The present case sheds light on the importance of prompt cytopathological diagnosis of xanthomatous lesions, especially in children and adolescents, as it can help prevent morbidity and mortality due to associated premature adverse cardiovascular and cerebrovascular events if left undiagnosed.

FEVR combined with macular heterotopia in children presenting as pseudo-exotropia: a case report and literature review.

Familial exudative retinopathy (FEVR) is a hereditary disease involving abnormal retinal vascular development in which macular heterotopia (MH) caused by mechanical-like pulling of the vitreous may lead to pseudo-strabismus. We describe the case of a 12-year-old male patient from China who presented to our hospital with a request for surgical correction of exotropia. Examination revealed that the strabismic appearance was due to MH, and dilated pupil examination of the peripheral fundus revealed that the blood vessels of the left eye and the macula were displaced toward the temporal retina by pulling, and further FFA examination was performed to diagnose FEVR. With good binocular vision and stereoscopic distance vision, corrective surgery for strabismus in this patient would have resulted in a hard-to-resolve diplopia. Therefore, it is important to identify FEVR combined with MH in clinical practice to avoid wrong diagnostic and treatment options.

Dysfunction of Calcyphosine-Like gene impairs retinal angiogenesis through the MYC axis and is associated with familial exudative vitreoretinopathy.

Familial exudative vitreoretinopathy (FEVR) is a severe genetic disorder characterized by incomplete vascularization of the peripheral retina and associated symptoms that can lead to vision loss. However, the underlying genetic causes of approximately 50% of FEVR cases remain unknown. Here, we report two heterozygous variants in calcyphosine-like gene (CAPSL) that is associated with FEVR. Both variants exhibited compromised CAPSL protein expression. Vascular endothelial cell (EC)-specific inactivation of Capsl resulted in delayed radial/vertical vascular progression, compromised endothelial proliferation/migration, recapitulating the human FEVR phenotypes. CAPSL-depleted human retinal microvascular endothelial cells (HRECs) exhibited impaired tube formation, decreased cell proliferation, disrupted cell polarity establishment, and filopodia/lamellipodia formation, as well as disrupted collective cell migration. Transcriptomic and proteomic profiling revealed that CAPSL abolition inhibited the MYC signaling axis, in which the expression of core MYC targeted genes were profoundly decreased. Furthermore, a combined analysis of CAPSL-depleted HRECs and c-MYC-depleted human umbilical vein endothelial cells uncovered similar transcription patterns. Collectively, this study reports a novel FEVR-associated candidate gene, CAPSL, which provides valuable information for genetic counseling of FEVR. This study also reveals that compromised CAPSL function may cause FEVR through MYC axis, shedding light on the potential involvement of MYC signaling in the pathogenesis of FEVR.

Defining familial longevity and developing a familial longevity score for unbiased epigenetic studies in a birth cohort.

Aim: Longevity accumulating in families has genetic and epigenetic components. To study early and unbiased epigenetic predictors of longevity prospectively, a birth cohort would be ideal. However, the original family longevity selection score (FLoSS) focuses on populations of elderly only.Methods: In the German birth cohort KUNO-Kids we assessed when information for such scores may be best collected and how to calculate an adapted FLoSS.Results: A total of 551 families contributed to adapted FLoSS, with a mean score of -0.15 (SD 2.33). Adapted FLoSS ≥7 as a marker of exceptional longevity occurred in 3.3% of families, comparable to original FLoSS in elderly.Conclusion: An adapted FLoSS from data collectable postnatally may be a feasible tool to study unbiased epigenetic predictors for longevity.

In the German birth cohort KUNO-Kids we assessed if and how a family longevity selection score may best be calculated to study unbiased epigenetic predictors for longevity in the future.

Attitudes of general and specialist French practitioners toward stage III-IV grade C periodontitis with familial aggregation.

The aim of this cross-sectional convenience sample survey was to assess attitudes of French dentists regarding stage III-IV grade C periodontitis in systemically healthy individuals. Among 225 dentists, 85.1% informed patients of the familial nature of periodontitis including 27.3% that recommended a consultation for the family. When dealing with a child who presented with severe periodontitis, 42.2% of the respondents did not advise examination of the parents. In addition, 39.1% of practitioners did not consider it possible to establish a family consultation. Finally, family factors are not often considered by French practitioners in the management of grade C periodontitis.

Pancreatic Cancer Screening among High-risk Individuals.

Pancreatic ductal adenocarcinoma (PDAC) continues to remain one of the leading causes of cancer-related death. Unlike other malignancies where universal screening is recommended, the same cannot be said for PDAC. The purpose of this study is to review which patients are at high risk of developing PDAC and therefore candidates for screening, methods/frequency of screening, and risk for these groups of patients.

Comparison of patients with familial chylomicronemia syndrome and multifactorial chylomicronemia syndrome.

CONTEXT: Patients with rare familial chylomicronemia syndrome (FCS) and relatively common multifactorial chylomicronemia syndrome (MCS) both express severe hypertriglyceridemia, defined as plasma triglyceride concentration ≥10 mmol/L (≥885 mg/dL). Clinically there can be confusion between the two conditions. OBJECTIVE: To compare clinical and biochemical phenotypes in patients with genotypically characterized FCS and MCS. METHODS: We performed targeted sequencing of DNA from 193 patients with severe hypertriglyceridemia, classified them as having either FCS or MCS and compared clinical and biochemical characteristics. RESULTS: FCS compared to MCS patients were significantly younger (31.4 ± 16.7 vs. 51.0 ± 11.3 years; P =0.003), with earlier age at symptom onset (15.0 ± 15.8 vs. 37.8 ± 8.8 years; P =0.00066), lower body mass index (23.3 ± 3.1 vs. 30.7 ± 5.0 kg/m2; P =0.000016), and higher prevalence of pancreatitis events (81.8% vs. 35.2%; P=0.003). Furthermore, FCS compared to MCS patients had a higher ratio of triglyceride to total cholesterol, i.e. 4.18 ± 0.92 vs 1.08 ± 0.51 (P <0.0001) and lower plasma apolipoprotein B, i.e. 0.56 ± 0.15 vs 1.02 ± 0.43 g/L (P <0.0001). MCS patients with heterozygous pathogenic variants had a relatively more severe clinical presentation than other MCS genetic subgroups. CONCLUSIONS: FCS patients have notable phenotypic differences from MCS patients, although there is overlap. While genetic analysis of patients with persistent severe hypertriglyceridemia can definitively diagnose FCS, 8.2% of MCS patients with sustained refractory hypertriglyceridemia behave functionally as if they have FCS, which should influence their eligibility for novel therapies for severe hypertriglyceridemia.

Considerations on expanding criminal offender DNA databases with Y-STR profiles.

Although national criminal offender DNA databases (NCODDs) including autosomal short tandem repeats (STRs) have been a successful tool to identify criminals for decades in many countries, yet there are many criminal cases they cannot solve. In cases with mixed male-female samples, particularly sexual assault, expanding NCODDs with Y-chromosomal STR (Y-STR) profiles allows database matching in the absence of autosomal STR profiles. Although Y-STR matches are not individual-specific, this can be largely overcome with rapidly mutating Y-STRs (RM Y-STR) allowing separation of paternally related men. Expanding NCODDs with Y-STR profiles is also beneficial for law enforcement in cases without known suspects via familial searching. Expanding NCODDs with Y-STR profiles may raise concerns about genetic privacy and fundamental human rights. A legal analysis of the European Convention on Human Rights revealed that when primarily for reidentifying convicted sex offenders, it would be in line with the case law of the European Court of Human Rights, while a generalized approach primarily for familial searching and involving all types of offenders may not. This paper aims to stimulate a debate among various stakeholders regarding the benefits and risks of expanding NCODDs with Y-STR profiles that in some countries has already been practically implemented.

Anthropometric measurements as a key diagnostic tool for familial partial lipodystrophy in women.

BACKGROUND: Familial Partial Lipodystrophy (FPLD) is a disease with wide clinical and genetic variation, with seven different subtypes described. Until genetic testing becomes feasible in clinical practice, non-invasive tools are used to evaluate body composition in lipodystrophic patients. This study aimed to analyze the different anthropometric parameters used for screening and diagnosis of FPLD, such as thigh skinfold thickness (TS), Köb index (Köbi), leg fat percentage (LFP), fat mass ratio (FMR) and leg-to-total fat mass ratio in grams (LTR), by dual-energy X-ray absorptiometry, focusing on determining cutoff points for TS and LFP within a Brazilian population. METHODS: Thirty-seven patients with FPLD and seventy-four healthy controls matched for body mass index, sex and age were studied. Data were collected through medical record review after signing informed consent. All participants had body fat distribution evaluated by skinfolds and DXA measures. Fasting blood samples were collected to evaluate glycemic and lipid profiles. Genetic studies were carried out on all patients. Two groups were categorized based on genetic testing and/or anthropometric characteristics: FPLD+ (positive genetic test) and FPLD1 (negative genetic testing, but positive clinical/anthropometric criteria for FPLD). RESULTS: Eighteen (48.6%) patients were classified as FPLD+, and 19 (51.4%) as FPLD1. Unlike what is described in the literature, the LMNA variant in codon 582 was the most common. Among the main diagnostic parameters of FPLD, a statistical difference was observed between the groups for, Köbi, TS, LFP, FMR, and LTR. A cutoff point of 20 mm for TS in FPLD women was found, which is lower than the value classically described in the literature for the diagnosis of FPLD. Additionally, an LFP < 29.6% appears to be a useful tool to aid in the diagnosis of these women. CONCLUSION: Combining anthropometric measurements to assess body fat distribution can lead to a more accurate diagnosis of FPLD. This study suggests new cutoff points for thigh skinfold and leg fat percentage in women with suspected FPLD in Brazil. Further studies are needed to confirm these findings.

Adrenal tumours in patients with pathogenic APC mutations: a retrospective study.

BACKGROUND: Adrenal tumours are associated with familial adenomatous polyposis (FAP). In the literature, most studies use the clinical definition of FAP (more than 100 adenomatous polyps found in endoscopic studies). However, not all patients that meet clinical criteria for FAP carry pathogenic mutations in the adenomatous polyposis coli (APC) gene, as there is genetic heterogeneity responsible for FAP with the polyposis sometimes explained by genetic and environmental factors other than pathogenic APC mutations. Reciprocally, not all the patients with pathogenic APC variants will fulfil the classic criteria of FAP. OBJECTIVE: This study aims to investigate the characteristics of adrenal tumours in patients with pathogenic or likely pathogenic APC variants and explore the hormonal function of these patients. METHOD: This is a retrospective cohort study. Patients with pathogenic or likely pathogenic APC variants were recruited and their radiological assessments were reviewed. Patient demographic data, APC variants, adrenal mass characteristics and hormonal testing results were collected. RESULT: The prevalence of adrenal mass was 26.7% (24/90) among patients with pathogenic or likely pathogenic APC variants. Using the classic definition, the prevalence was 32.4% (22/68). Four patients had adrenal hormone testing, two of which had Conn's syndrome and two had nonspecific subclinical results. CONCLUSION: In our cohort, the prevalence of adrenal tumours among patients with pathogenic and likely pathogenic APC mutations is at least twice to three times higher than the general population prevalence reported from international population-based studies. The hormonal functions of patients with pathogenic APC variants and adrenal tumours can be investigated with routine testing in further research.

Implementation of long-read sequencing for routine molecular diagnosis of familial mediterranean fever.

Background: Long-read sequencing technology, widely used in research, is proving useful in clinical diagnosis, especially for infectious diseases. Despite recent advances, it hasn't been routinely applied to constitutional human diseases. Long-read sequencing detects intronic variants and phases variants, crucial for identifying recessive diseases. Methods: We integrated long-read sequencing into the clinical diagnostic workflow for the MEFV gene, responsible for familial Mediterranean fever (FMF), using a Nanopore-based workflow. This involved long-range PCR amplification, native barcoding kit library preparation, GridION sequencing, and in-house bioinformatics. We compared this new workflow against our validated method using 39 patient samples and 3 samples from an external quality assessment scheme to ensure compliance with ISO15189 standards. Results: Our evaluation demonstrated excellent performance, meeting ISO15189 requirements for reproducibility, repeatability, sensitivity, and specificity. Since October 2022, 150 patient samples were successfully analyzed with no failures. Among these samples, we identified 13 heterozygous carriers of likely pathogenic (LP) or pathogenic (P) variants, 1 patient with a homozygous LP/P variant in MEFV, and 4 patients with compound heterozygous variants. Conclusion: This study represents the first integration of long-read sequencing for FMF clinical diagnosis, achieving 100 % sensitivity and specificity. Our findings highlight its potential to identify pathogenic variants without parental segregation analysis, offering faster, cost-effective, and accurate clinical diagnosis. This successful implementation lays the groundwork for future applications in other constitutional human diseases, advancing precision medicine.

Novel Mutation in the Calcium-Sensing Receptor Gene Associated With Familial Hypocalciuric Hypercalcemia.

We present a case of a 75-year-old woman with persistent hypercalcemia (serum calcium 10.7 mg/dL, ionized calcium 1.37 mmol/L), elevated parathyroid hormone levels (86.6 pg/mL), and significantly low 24-hour urinary calcium excretion (<11 mg/24 hours). Genetic testing identified a novel heterozygous variant in the calcium-sensing receptor (CaSR) gene, c.3166G>C (p. Val1056Leu). The patient's biochemical profile and the identification of the CaSR variant support the diagnosis of familial hypocalciuric hypercalcemia (FHH). The novel c.3166G>C (p.Val1056Leu) variant has not been previously reported in FHH or other CaSR-associated conditions. Its presence in this patient suggests a potential role in the clinical manifestation of FHH. However, it is currently classified as a variant of undetermined significance (VUD) in the ClinVar database, necessitating further research on the clinical relevance of this variant in FHH. This case highlights the significance of genetic testing in diagnosing FHH and the potential clinical impact of discovering novel CaSR gene mutations. Further research on the genetics associated with FHH is necessary to better understand the condition, detect it early, and manage it effectively, thereby improving patient care and outcomes.

Familial Acute Promyelocytic Leukemia: A Case Report and Review of the Literature.

Acute promyelocytic leukemia (APL) is characterized by a reciprocal translocation t (15;17) (q24;q21), which leads to the fusion of PML and RARα genes known as PML-RARα fusion. A few cases of potentially hereditary leukemia-related genes in APL have been reported, but no instances of familial aggregation of APL have been documented. Here, we describe a family in whom two members successively affected by APL。The potential familial association observed in these two cases of APL highlights the need for further investigation and more definitive genetic lineage tracing in order to understand the genetic basis of this disease.

Identification and functional validation of a novel pathogenic POT1 germline variant p.G95V in familial melanoma.

POT1 variants have been identified in familial melanoma (FM) as well as a number of other germline and somatic malignancies. The functional validation of variants identified from the screening of patients with melanoma gene susceptibility panels is key to understanding the clinical significance of identified variants. Here we report a novel, likely pathogenic POT1 missense variant (p.G95V) in FM and investigate its functional impact. We demonstrate loss of function owing to the inability of the mutant POT1 protein to bind telomeric DNA compared to its wild-type counterpart. This study provides important functional validation of a novel POT1 variant in FM.