CES (Clinical Exome Sequencing) is a method that we use to diagnose rare diseases with nonspesific clinical features. Besides primary indication for testing genetic information may be detected about ...diseases which have not yet emerged. ACMG guidelines recommend to report pathogenic variations in medically actionable 59 genes. In this study we evaluated CES data of 622 cases which were tested for various indications. According to ACMG recommendations 59 genes were screened for reportable variations. The detected variations were reviewed using distinct databases and ACMG variation classification guidelines. Among 622 cases 13 (2.1%) had reportable variations including oncogenetic, cardiogenetic disorders, and malignant hyperthermia susceptibility-related genes. In 15 cases (2.4%) heterozygous pathogenic and likely pathogenic variations were detected in genes showing autosomal recessive inheritance. Ten novel variations causing truncated protein or splicing defect were reported. We detected 11 variations having conflicting interpretations in databases and 30 novel variations, predicted as likely pathogenic via insilico analysis tools which further evaluations are needed. As to our knowledge this is the first study investigating secondary findings in Turkish population. To extract the information that may lead to prevent severe morbidities and mortalities from big data is a valuable and lifesaving effort. Results of this study will contrbute to existing knowledge about secondary findings in exome sequencing and will be a pioneer for studies in Turkish population.
Vitamin D-dependent rickets type IA (VDDR-IA) is caused by biallelic mutations in
CYP27B1
. Data regarding genotype–phenotype correlation in VDDR-IA are scarce. Here, we aimed to investigate ...clinical/genotypic features and long-term follow-up of 13 new cases with VDDR-IA and genotype–phenotype correlation of reported cases in the literature. Thirteen patients with VDDR-IA were evaluated. Eight patients had reached their final height at the time of the study and, for whom, long-term outcome data were analyzed. Further, all VDDR-IA patients in the literature (n:183) were analyzed and clinical–genetic features were recorded. The median age of diagnosis was 2.55 ± 1.13 (1.0–12) years. Initial diagnoses before referral to our clinic were nutritional rickets (n:7), hypophosphatemic rickets (n:2), and pseudohypoparathyroidism (n:1). All had biochemical evidence suggestive of VDDR-IA; except one with elevated 1,25(OH)
2
D3 and another with hyperphosphatemia, in whom pseudohypoparathyroidism was excluded with molecular tests. Combined analyses of our cohort and other series in the literature demonstrated that three most common
CYP27B1
mutations are p.F443Pfs*24, c.195 + 2T > G, and p.V88Wfs*71. In Turkish population, p.K192E mutation along with the former two is the most common mutations. Comparison of clinical features demonstrated that c.195 + 2T > G mutation causes the most severe and p.K192E mutation causes the least severe phenotype with respect to age and height at presentation and calcitriol requirement. We found a clear genotype–phenotype correlation in VDDR-IA, notably
CYP27B1
intronic c.195 + 2T > G mutation causes a more severe phenotype with lower height SDS at presentation and, higher calcitriol requirement, while less severe phenotype occurs in p.K192E mutation.
Purpose
Premature ovarian insufficiency (POI) is a heterogeneous disorder characterized by the cessation of menstrual cycles before the age of 40 years due to the depletion or dysfunction of the ...ovarian follicles. POI is a highly heterogeneous disease in terms of etiology. The aim of this study is to reveal the genetic etiology in POI patients.
Methods
A total of 35 patients (mean age: 27.2 years) from 28 different families diagnosed with POI were included in the study. Karyotype,
FMR1
premutation analysis, single nucleotide polymorphism (SNP) array, and whole-exome sequencing (WES) were conducted to determine the genetic etiology of patients.
Results
A total of 35 patients with POI were first evaluated by karyotype analysis, and chromosomal anomaly was detected in three (8.5%) and
FMR1
premutation was detected in six patients (17%) from two different families. A total of 29 patients without
FMR1
premutation were included in the SNP array analysis, and one patient had a 337-kb deletion in the chromosome 6q26 region including
PARK2
gene, which was thought to be associated with POI. Twenty-nine cases included in SNP array analysis were evaluated simultaneously with WES analysis, and genetic variant was detected in 55.1% (16/29).
Conclusion
In the present study, rare novel variants were identified in genes known to be associated with POI, which contribute to the mutation spectrum. The effects of detected novel genes and variations on different pathways such as gonadal development, meiosis and DNA repair, or metabolism need to be investigated by experimental studies. Molecular etiology allows accurate genetic counseling to the patient and family as well as fertility planning.
Biallelic loss of function mutations in the
CLDN16
gene cause familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), and chronic kidney disease. Here we report two cases of FHHNC ...with diverse clinical presentations and hypercalcemia in one as a novel finding. Pt#1 initially presented with urinary tract infection and failure to thrive at 5.5 months of age to another center. Bilateral nephrocalcinosis, hypercalcemia (Ca: 12.2 mg/dl), elevated parathyroid hormone (PTH) level, and hypercalciuria were detected. Persistently elevated PTH with high/normal Ca levels led to subtotal-parathyroidectomy at the age of 2.5. However, PTH levels remained elevated with progressive deterioration in renal function. At 9-year-old, she was referred to us for evaluation of hyperparathyroidism and, hypomagnesemia together with hypercalciuria, elevated PTH with normal Ca levels, and medullary nephrocalcinosis were detected. Compound heterozygosity of
CLDN16
variants (c.715G>A, p.G239R; and
novel
c.360C>A, p.C120*) confirmed the diagnosis. Pt#2 was a 10-month-old boy, admitted with irritability and urinary crystals. Hypocalcemia, hypophosphatemia, elevated PTH and ALP, low 25(OH)D levels, and radiographic findings of rickets were detected. However, additional findings of hypercalciuria and bilateral nephrocalcinosis were inconsistent with the nutritional rickets. Low/normal serum Mg levels suggested the diagnosis of FHHNC which was confirmed genetically as a homozygous missense (c.602G > A; p.G201E) variant in
CLDN16
. Yet, hypocalcemia and hypomagnesemia persisted in spite of treatment. In conclusion, FHHNC may present with diverse clinical features with mild hypomagnesemia leading to secondary hyperparathyroidism with changing Ca levels from low to high. Early and accurate clinical and molecular genetic diagnosis is important for proper management.
Heterogeneity in symptoms associated with COVID‐19 in infected patients remains unclear. ACE2 and TMPRSS2 gene variants are considered possible risk factors for COVID‐19. In this study, a ...retrospective comparative genome analysis of the ACE2 and TMPRSS2 variants from 946 whole‐exome sequencing data was conducted. Allele frequencies of all variants were calculated and filtered to remove variants with allele frequencies lower than 0.003 and to prioritize functional coding variants. The majority of detected variants were intronic, only two ACE2 and three TMPRSS2 nonsynonymous variants were detected in the analyzed cohort. The main ACE2 variants that putatively have a protective or susceptibility effect on SARS‐CoV‐2 have not yet been determined in the Turkish population. The Turkish genetic makeup likely lacks any ACE2 variant that increases susceptibility to SARS‐CoV‐2 infection. TMPRSS2 rs75603675 and rs12329760 variants that were previously defined as common variants that have different allele frequencies among populations and may have a role in SARS‐CoV‐2 attachment to host cells were determined in the population. Overall, these data will contribute to the formation of a national variation database and may also contribute to further studies of ACE2 and TMPRSS2 in the Turkish population and differences in SARS‐CoV‐2 infection among other populations.
Raine Syndrome (RS) is caused by biallelic loss-of-function mutations in
FAM20C
gene and characterized by hypophosphatemia, typical facial and skeletal features. Subperiosteal bone formation and ...generalized osteosclerosis are the most common radiological findings. Here we present a new case with RS. A 9-month-old male patient on a home-type ventilator was referred for hypophosphatemia. He was born with a weight of 3800 g to non-consanguineous parents. Prenatal ultrasound had demonstrated nasal bone agenesis. A large anterior fontanel, frontal bossing, exophthalmos, hypoplastic nose, high arched palate, low set ears, triangular mouth, and corneal opacification were detected on physical examination. Serial skeletal X-rays revealed diffuse osteosclerosis at birth which was gradually decreased by the age of 5 months with subperiosteal undermineralized bone formation and medullary space of long bone could be distinguishable with bone-within-a-bone appearance. At 9 months of age, hand X-ray revealed cupping of the ulna with loose radial bone margin with minimal fraying and osteopenia. Cranial computed tomography scan showed bilateral periventricular calcification and hydrocephalus in progress. The clinical, laboratory, and radiological examinations were consistent with RS. Molecular analyses revealed a compound heterozygous mutation in
FAM20C
gene (a known pathogenic mutation, c.1645C > T, p.Arg549Trp; and a novel c.863 + 5 G > C variant). The patient died due to respiratory failure at 17 months of age. This case allowed us to demonstrate natural progression of skeletal features in RS. Furthermore, we have described a novel
FAM20C
variant causing RS. Previous literature on RS is also reviewed.
Breast cancer (BC) persists as the predominant malignancy globally, standing as the foremost cause of cancer-related mortality among women. Despite notable advancements in prevention and treatment, ...encompassing the incorporation of targeted immunotherapies, a continued imperative exists for the development of innovative methodologies. These methodologies would facilitate the identification of women at heightened risk, enhance the optimization of therapeutic approaches, and enable the vigilant monitoring of emergent treatment resistance. Circulating microRNAs (miRNAs), found either freely circulating in the bloodstream or encapsulated within extracellular vesicles, have exhibited substantial promise for diverse clinical applications. These applications range from diagnostic and prognostic assessments to predictive purposes. This study aimed to explore the potential associations between BRCA mutations and specific miRNAs (miR-21, miR-155, miR-126, and miR-200c) expression that are known to be dysregulated in BC patient samples. Our findings indicate a robust correlation between miRNA expression status and disease subtypes. We found a correlation between the expression status of miRNAs and distinct disease subtypes. Intriguingly, however, no significant associations were discerned between disease status, subtypes, or miRNA expression levels and the presence of BRCA mutations. To advance the validation of miRNAs as clinically relevant biomarkers, additional investigations within larger and meticulously selected patient cohorts are deemed imperative. These microRNA entities hold the potential to emerge as groundbreaking and readily accessible tools, poised for seamless integration into the landscape of clinical practice.
Ovarian cancer (OC) is the main cause of gynecological cancer mortality in most developed countries. microRNA (miR) expression dysregulation has been highlighted in human cancers, and miR-34a is ...found to be downregulated and associated with inhibition of tumor growth and invasion in several malignancies, including OC. The winged helix transcription factor forkhead box P1 (FOXP1) is reported as either an oncogene or tumor suppressor in various cancers. This study aimed to elucidate potential clinical and biological associations of miR-34a and transcription factor FOXP1 in OC. We investigated nine OC patients’ blood samples and two OC cell lines (SKOV-3 and OVCAR-3) using quantitative real-time reverse transcription polymerase chain reaction (RT-qPCR) to determine both miR-34a and FOXP1 expressions. We have found that miR-34a and FOXP1 are reversely correlated in both in vitro and in vivo. Inhibition of miR-34a transiently led to upregulation of FOXP1 mRNA expression and increased cellular invasion in vitro. Our data indicate that miR-34a could be a potential biomarker for improving the diagnostic efficiency of OC, and miR-34a overexpression may reduce OC pathogenesis by targeting FOXP1.
Background
Cubilin is one of the receptor proteins responsible for reabsorption of albumin in proximal tubules and is encoded by the
CUBN
gene. We aimed to evaluate clinical and genetic ...characterization of six patients with proteinuria who had
CUBN
mutations.
Methods
Patients’ characteristics, serum creatinine, albumin, vitamin B
12
levels, urine analysis, spot urine protein/creatinine, microalbumin/creatinine, beta-2 microglobulin/creatinine ratios, estimated glomerular filtration rates (eGFR), treatments, kidney biopsies, and genetic analyses were evaluated.
Results
Six patients (2 female, 4 male) with an incidental finding of proteinuria were evaluated. Mean admission age and follow-up time were 7.3 ± 2.9 and 6.5 ± 5.6 years, respectively. Serum albumin, creatinine, and eGFR were normal; urine analysis revealed no hematuria, and C3, C4, ANA, and anti-DNA were negative; kidney ultrasonography was normal for all patients. Urine protein/creatinine was 0.9 ± 0.3 mg/mg, and microalbumin was high in all patients. Serum vitamin B
12
was low in two patients and normal in four. Kidney biopsy was performed in four patients, three demonstrated normal light microscopy, and there was one focal segmental glomerulosclerosis (FSGS). Genetic tests revealed four homozygous and two compound heterozygous mutations in the C-terminal part of cubilin. All patients had normal eGFR and still had non-nephrotic range proteinuria at last visit.
Conclusions
CUBN
gene mutations should be considered in patients with isolated non-nephrotic range proteinuria and normal kidney function. Diagnosing these patients, who are thought to have a better prognosis, is important in terms of avoiding unnecessary treatment and predicting prognosis.
CUBN
gene mutations may also present as FSGS which extends the spectrum of renal manifestation of these patients.
Graphical abstract
A higher resolution version of the Graphical abstract is available as
Supplementary information
PDF
