Medical Genetics Guidelines Research Articles

Phenotype driven molecular genetic test recommendation for diagnosing pediatric rare disorders

Patients with rare diseases often experience prolonged diagnostic delays. Ordering appropriate genetic tests is crucial yet challenging, especially for general pediatricians without genetic expertise. Recent American College of Medical Genetics (ACMG) guidelines embrace early use of exome sequencing (ES) or genome sequencing (GS) for conditions like congenital anomalies or developmental delays while still recommend gene panels for patients exhibiting strong manifestations of a specific disease. Recognizing the difficulty in navigating these options, we developed a machine learning model trained on 1005 patient records from Columbia University Irving Medical Center to recommend appropriate genetic tests based on the phenotype information. The model achieved a remarkable performance with an AUROC of 0.823 and AUPRC of 0.918, aligning closely with decisions made by genetic specialists, and demonstrated strong generalizability (AUROC:0.77, AUPRC: 0.816) in an external cohort, indicating its potential value for general pediatricians to expedite rare disease diagnosis by enhancing genetic test ordering.

Genetic and Clinical Characteristics of 185 Japanese Children with 46,XY Differences of Sex Development.

46,XY differences of sex development (DSD) are heterogeneous in etiology. The detailed phenotypes of 46,XY DSD patients with monogenic disorders have not been fully elucidated. To estimate the proportion of monogenic disorders in 46,XY DSD and to characterize the clinical phenotypes of patients with monogenic disorders. A total of 185 Japanese patients (178 families) were enrolled. We sequenced 25 genes related to 46,XY DSD, and assessed the pathogenicity of the identified sequence variants according to the American College of Medical Genetics and Genomics guidelines, supplemented by in silico or in vitro analyses. We analyzed the clinical phenotypes of patients with monogenic disorders, with particular attention to the external or internal genitalia. We identified 51 patients (47 families) with any monogenic disorders (26%), who possessed pathogenic variants in AR (11%), SRD5A2 (4.5%), NR5A1 (4.0%), SRY (2.8%), WT1 (1.1%), STAR (1.1%), CYP17A1 (0.56%), HSD3B2 (0.56%), or MAP3K1 (0.56%). The proportion of monogenic disorders was significantly higher in subjects with detected Müllerian derivatives (57%) than in those undetected (26%) (P = 0.029), in subjects with female-typical genitalia (91%) than those with ambiguous genitalia (19%) (P < 0.001). The proportion of monogenic disorders in Japanese 46,XY DSD patients was approximately 26%. Monogenic disorders were frequent among patients with severe undermasculinization of the external or internal genitalia.

A Comprehensive Target Panel Allows to Extend the Genetic Spectrum of Neuroendocrine Tumors.

Neuroendocrine tumors (NETs) frequently have a genetic basis, and the range of genes implicated in NET development continues to expand. Application of targeted gene panels (TGPs) in next-generation sequencing is a central strategy for elucidating novel variants associated with NET development. In this study, we conducted comprehensive molecular genetic analyses using TGP on a cohort of 93 patients diagnosed with various NETs subtypes, mainly accompanied by various endocrine syndromes: insulinoma (n = 26), pheochromocytoma and paraganglioma (PPGL) (n = 38), parathyroid adenoma (n = 18, including three with insulinoma), and NETs of other locations (n = 14). The TGP encompassed genes linked to diverse NETs and other hereditary endocrine disorders, with subsequent variant classification according to the American College of Medical Genetics and Genomics guidelines. Among the identified variants, 20 were found in genes previously linked to specific tumor types, and 10 were found in genes with a limited likelihood and unclear molecular mecanisms of association with observed NETs. Remarkably, 13 variants were discovered in genes not previously associated with the NETs observed in our patients. These genes, such as ABCC8, KCNJ11, KLF11, HABP2, and APC, were implicated in insulinoma; ZNRF3, GNAS, and KCNJ5 were linked with PPGL; parathyroid adenomas were related to variants in SDHB and TP53; while NETs of other locations displayed variants in APC and ABCC8. Our study demonstrates that utilizing broad TGP in examining patients with various functioning NETs facilitates the identification of new germinal variants in genes that may contribute to the diseases. The verification of revealed findings requires research in vaster sample.

A novel frameshift mutation in the DIAPH1 gene causes a Chinese family autosomal dominant nonsyndromic hearing loss: Mutation in DIAPH1 causes hearing loss

ObjectiveThis study reports a novel heterozygous, likely truncating mutation in the diaphanous homolog 1 (DIAPH1) gene associated with non-syndromic hearing loss. MethodsFamily members underwent audiological and imaging assessments, whole-exome sequencing (WES), and Sanger sequencing. ResultsSensorineural hearing loss was observed in all five individuals, with severity ranging from mild to severe. None of the affected patients reported vestibular complaints, and routine blood tests showed normal platelet counts. Whole-exome sequencing (WES) revealed a novel frameshift variation, c.3555delA (p.Gln1185Hisfs*3), in exon 26 of the DIAPH1 gene. This variation co-segregated with the hearing-impaired phenotype in the family. The data collected support the classification of c.3555delA as a genetic etiology of hereditary hearing loss according to the American College of Medical Genetics and Genomics guidelines. ConclusionWe identified a novel pathogenic mutation in the DIAPH1 gene, thereby expanding the mutation spectrum associated with hearing loss.

Exon Sequencing of HNF1β in Chinese Patients with Early-Onset Diabetes.

Maturity-onset diabetes of the young (MODY) due to variants of hepatocyte nuclear factor 1-beta (HNF1β) (MODY5) has not been well studied in the Chinese population. This study aimed to estimate its prevalence and evaluate the application of a clinical screening method (Faguer score) in Chinese early-onset diabetes (EOD) patients. Among 679 EOD patients clinically diagnosed with type 2 diabetes mellitus (age at diagnosis ??0 years), the exons of HNF1β were sequenced. Functional impact of rare variants was evaluated using a dual-luciferase reporter system. Faguer scores ?? prompted multiplex ligation-dependent probe amplification (MLPA) for large deletions. Pathogenicity of HNF1β variants was assessed following the American College of Medical Genetics and Genomics (ACMG) guidelines. Two rare HNF1β missense mutations (E105K and G454R) were identified by sequencing in five patients, showing functional impact in vitro. Another patient was found to have a whole-gene deletion by MLPA in 22 patients with the Faguer score above 8. Following ACMG guidelines, six patients carrying pathogenic or likely pathogenic variant were diagnosed with MODY5. The estimated prevalence of MODY5 in Chinese EOD patients was approximately 0.9% or higher. MODY5 is not uncommon in China. The Faguer score is helpful in deciding whether to perform MLPA analysis on patients with negative sequencing results.

Exome sequencing data reanalysis of 200 hypertrophic cardiomyopathy patients: the HYPERGEN French cohort 5 years after the initial analysis.

Approximately half of hypertrophic cardiomyopathy (HCM) patients lack a precise genetic diagnosis. The likelihood of identifying clinically relevant variants increased over time. In this study, we conducted a gene-centric reanalysis of exome data of 200 HCM cases 5 years after the initial analysis. This reanalysis prioritized genes with a matched HCM entry in the OMIM database and recently emerging HCM-associated genes gathered using a text mining-based literature review. Further classification of the identified genes and variants was performed using the Clinical Genome Resource (ClinGen) resource and American College of Medical Genetics and Genomics (ACMG) guidelines to assess the robustness of gene-disease association and the clinical actionability of the prioritized variants. As expected, the majority of patients carried variants in MYBPC3 and MYH7 genes, 26% (n = 51) and 8% (n = 16), respectively, in accordance with the initial analysis. The vast majority of pathogenic (P) and likely pathogenic (LP) variants were found in MYBPC3 (22 out of 40 variants) and MYH7 (8 out of 16 variants) genes. Three genes-not included in the initial analysis-were identified: SVIL, FHOD3, and TRIM63. Considering only patients with unique variants in the last three genes, there was a 9% enhancement in variant identification. Importantly, SVIL variant carriers presented apical and septal HCM, aortopathies, and severe scoliosis for one patient. Ten patients (5%) carried variants in the FHOD3 gene, six in hotspot regions (exons 12 and 15). We identified seven variants within the TRIM63 gene in 12 patients (6%). Homozygous variants were detected in 2.5% of the cohort in MYBPC3 (n = 1), MYL3 (n = 1), and TRIM63 (n = 3) genes. Our study revealed that no variants were found in the ACTC1, TPM1, and TNNI3 genes in the HYPERGEN cohort. However, we identified variants in five out of the eight HCM core genes, with a high prevalence in young patients. We identified variants in three recent HCM-associated genes (SVIL, FHOD3, and TRIM63) in 35 patients, with 18 patients carrying unique variants (9%). Our results further emphasize the usefulness of exome data reanalysis, particularly in genotype-negative patients.

Whole-exome sequencing to identify causative variants in cases of sudden cardiac death below 50 years

Abstract Background Sudden cardiac death (SCD) in individuals under 50 frequently remains unexplained, especially when no structural cardiac abnormalities are present, a condition known as sudden arrhythmic death (SAD). This study assesses the utility of whole exome sequencing (WES) with a comprehensive gene panel in elucidating the genetic foundations of SCD. Methods SCD autopsy cases from a university hospital (1995-2023) were analysed both retrospectively and prospectively. WES was conducted on 32 cases, employing a virtual panel of 1,304 genes. Variant prioritization was based on pathogenicity according to American College of Medical Genetics and Genomics guidelines. Results WES unveiled causative variants in 22 out of 32 cases (68% diagnostic yield). Of these, 12 cases (38%) possessed pathogenic or likely pathogenic variants, and 17 highly suspicious variants of uncertain significance (VUS/LP) were identified in 10 patients (31%). The diagnostic yield of our comprehensive panel (69%) surpassed that of major susceptibility gene panels, with 22% for primary susceptibility genes and 56% for the TruSight Cardio Panel. Half of the cases had multiple variants, underscoring the genetic complexity of SCD. Of the genes analysed, 18 were associated with cardiac disease on OMIM or ClinGen, while 9, unique to our panel, were linked to cardiac function but had disputed or limited disease associations. Conclusions WES with a specific gene panel, a scheme for variant prioritization, and a comprehensive, multidisciplinary approach to variant interpretation is an effective approach to genetic testing in SCD cases ≤50 years.Added value of WES

Clinical and genetic analysis of autosomal dominant polycystic liver disease

Objective: To analyze and clarify the clinical and pathogenic gene variation and genetic etiology of polycystic liver disease. Methods: The proband clinical data and family history were collected. Whole-exome sequencing technology was used to detect the proband gene variations. Fluorescence quantitative PCR validation was performed on the proband and his family to screen out pathogenic gene variation. Results: A multiple liver cyst was found in an 18-year-old male proband during a physical examination. There were no abnormalities in his liver function, and both his father and grandfather had multiple liver cysts without any obvious discomfort or other special manifestations. Whole exome sequencing suggested a heterozygous deletion in exon 1 (Exon 1) of the SEC63 gene in the proband. Real-time fluorescence quantitative PCR confirmed that the heterozygous deletion variation of the SEC63 gene Exon 1 of the proband came from his father, and the same heterozygous deletion was detected in his grandfather. The gene variant had a pathogenic variation that had been rarely reported before and was in accordance with the the American college of Medical Genetics and Genomics (ACMG) guidelines. Conclusions: The genetic etiology of this autosomal dominant polycystic liver disease has been clarified, and the heterozygous deletion of Exon1 of the SEC63 gene is a newly discovered gene variation that broadens the variation spectrum of the SEC63 gene.

Whole exome sequencing in patients with childhood-onset systemic lupus erythematosus: Results from a Croatian national study.

The purpose of this study was to identify new and low-frequency gene variants using whole exome sequencing (WES) in patients with childhood-onset systemic lupus erythematosus (cSLE), that may be involved in the pathogenesis of SLE. We performed WES on selected 17 trios (in some cases including other informative family members) in which the proband presented with severe, atypical clinical features, resistance to conventional therapy, a family pattern of occurrence and/or syndromic characteristics. After performing WES and analysis of gene variants, 17 novel and/or low-frequency variants were identified in 7 patients. One variant was classified as pathogenic (KMT2D, NM_003482.3:c.8626delC, predicted to truncate the protein p.(Gln2876Serfs*34)) and two as likely pathogenic according to the American College of Medical Genetics and Genomics classification guidelines (ADAR, NM_001111.3:c.2815A>G, predicted to encode p.(Ile939Val); BLK, NM_001715.2:c.211G>A, predicted to encode p.(Ala71Thr)). The other variants remain of uncertain significance at this point of time. WES is an important diagnostic and research instrument, producing a growing list of likely genes and gene variants that may be of relevance in the pathogenesis of cSLE and potentially point to novel therapeutic targets.

A case of alternating hemiplegia in 2-month-old children with nystagmus as the first symptom: A case report.

This case report delves into the rare neurological condition known as alternating hemiplegia of childhood (AHC), focusing on its clinical manifestations, diagnostic approaches, and treatment options. AHC typically presents in infants under the age of 18 months with intermittent episodes of hemiplegia, often triggered by stressors such as environmental changes, bathing, or emotional stress. Recognizing the clinical features of AHC is crucial for early identification and intervention. The paper presents a case of a 2-month-old child with nystagmus as the initial symptom, followed by limb movement disorder in the left upper limb and weakness in the right limbs. The child's condition did not improve with treatment at an external hospital, highlighting the complexity of the disease and the need for specialized care. After a comprehensive review of the patient's medical history, physical examination, and imaging studies, the child was diagnosed with AHC. The diagnosis was confirmed through video electroencephalogram and whole-exome gene detection, which revealed a de novo mutation in the ATP1A3 gene, identified as pathogenic according to the American College of Medical Genetics and Genomics guidelines. The child was admitted to Peking University First Hospital and treated with levetiracetam and flunarizine oral administration. These medications were chosen for their efficacy in managing the symptoms of AHC, particularly the hemiplegic episodes. Post-treatment, the child experienced a reduction in the frequency and intensity of hemiplegic attacks compared to the initial stage. However, the child still exhibited paroxysmal symptoms and abnormal eye movements, and developmental milestones were delayed, indicating the need for ongoing care and monitoring. This case underscores the importance of early recognition and prompt intervention in managing children with AHC. The varied clinical presentations of AHC necessitate vigilance for early differential diagnosis. Although AHC is currently incurable, appropriate treatment can mitigate the impact of complications and improve the long-term quality of life for affected children, facilitating better societal integration.

Investigating the prevalence of MFN2 mutations in amyotrophic lateral sclerosis: insights from an Italian cohort.

The MFN2 gene encodes mitofusin 2, a key protein for mitochondrial fusion, transport, maintenance and cell communication. MFN2 mutations are primarily linked to Charcot-Marie-Tooth disease type 2A. However, a few cases of amyotrophic lateral sclerosis and amyotrophic lateral sclerosis/frontotemporal dementia phenotypes with concomitant MFN2 mutations have been previously reported. This study examines the clinical and genetic characteristics of an Italian cohort of amyotrophic lateral sclerosis patients with rare, non-synonymous MFN2 mutations. A group of patients (n = 385) diagnosed with amyotrophic lateral sclerosis at our Neurology Units between 2008 and 2023 underwent comprehensive molecular testing, including MFN2. After excluding pathogenic mutations in the main amyotrophic lateral sclerosis-related genes (i.e. C9orf72, SOD1, FUS and TARDBP), MFN2 variants were classified based on the American College of Medical Genetics and Genomics guidelines, and demographic and clinical data of MFN2-mutated patients were retrieved. We identified 12 rare, heterozygous, non-synonymous MFN2 variants in 19 individuals (4.9%). Eight of these variants, carried by nine patients (2.3%), were either pathogenic, likely pathogenic or variants of unknown significance according to the American College of Medical Genetics and Genomics guidelines. Among these patients, four exhibited a familial pattern of inheritance. The observed phenotypes included classic and bulbar amyotrophic lateral sclerosis, amyotrophic lateral sclerosis/frontotemporal dementia, flail arm, flail leg and progressive muscular atrophy. Median survival after disease onset was extremely variable, ranging from less than 1 to 13 years. This study investigates the prevalence of rare, non-synonymous MFN2 variants within an Italian cohort of amyotrophic lateral sclerosis patients, who have been extensively investigated, enhancing our knowledge of the underlying phenotypic spectrum. Further research is needed to understand whether MFN2 mutations contribute to motor neuron disease and to what extent. Improving our knowledge regarding the genetic basis of amyotrophic lateral sclerosis is crucial both in a diagnostic and therapeutic perspective.

Next-generation sequencing in Charcot-Marie-Tooth: a proposal for improvement of ACMG guidelines for variant evaluation

BackgroundThe application of massive parallel sequencing technologies in the molecular analysis of Charcot-Marie-Tooth (CMT) has enabled the rapid and cost-effective identification of numerous potentially significant variants for diagnostic purposes. The...

Maple syrup urine disease diagnosis in Brazilian patients by massive parallel sequencing

Biallelic pathogenic variants cause maple syrup urine disease (MSUD) in one of the branched-chain α-keto acid dehydrogenase (BCKDH) complex genes (BCKDHA, BCKDHB, DBT, DLD, and PPM1K) leading to the accumulation of leucine, isoleucine, and valine. This study aimed to perform a molecular diagnosis of Brazilian patients with MSUD using gene panels and massive parallel sequencing. Eighteen Brazilian patients with a biochemical diagnosis of MSUD were analyzed by massive parallel sequencing in the Ion PGM Torrent Server using a gene panel with the BCKDHA, BCKDHB, and DBT genes. The American College of Medical Genetics and Genomics guidelines were used to determine variant pathogenicity. Thirteen patients had both variants found by massive parallel sequencing, whereas 3 patients had only one variant found. In 2 patients, the variants were not found by this analysis. These 5 patients required additional Sanger sequencing to confirm their genotype. Twenty-five pathogenic variants were identified in the 3 MSUD-related genes (BCKDHA, BCKDHB, and DBT). Most variants were present in the BCKDHB gene, and no common variants were found. Nine novel variants were observed: c.922 A > G, c.964C > A, and c.1237 T > C in the BCKDHA gene; and c.80_90dup, c.384delA, c.478 A > T, c.528C > G, c.977 T > C, and c.1039-2 A > G in the BCKDHB gene. All novel variants were classified as pathogenic. Molecular modeling of the novel variants indicated that the binding of monomers was affected in the BCKDH complex tetramer, which could lead to a change in the stability and activity of the enzyme. Massive parallel sequencing with targeted gene panels seems to be a cost-effective method that can provide a molecular diagnosis of MSUD.

Phenotypic features, prevalence of KCNJ11-MODY in Chinese patients with early-onset diabetes and a literature review.

Gain-of-function (GOF) variants of KCNJ11 cause neonate diabetes and maturity-onset diabetes of the young (KCNJ11-MODY), while loss-of-function (LOF) variants lead to hyperinsulinemia hypoglycemia and subsequent diabetes. Given the limited research of KCNJ11-MODY, we aimed to analyse its phenotypic features and prevalence in Chinese patients with early-onset type 2 diabetes (EOD). We performed next-generation sequencing on 679 Chinese EOD patients to screen for KCNJ11 exons variants. Bioinformatics prediction and the American College of Medical Genetics and Genomics guidelines was used to determine the pathogenicity and diagnosed KCNJ11-MODY. A literature review was conducted to investigate the phenotypic features of KCNJ11-MODY. We identified six predicted deleterious rare variants in six EOD patients (0.88%). They were classified as uncertain significance (variant of uncertain significance [VUS]), but more common in this EOD cohort than a general Chinese population database, however, without significant difference (53/10,588, 0.50%) (p = .268). Among 80 previously reported patients with KCNJ11-MODY, 23.8% (19/80) carried 9 (32.1%) LOF variants, who had significantly older age at diagnosis, higher birthweight and higher fasting C-peptide compared to patients with GOF variants. Many patients carrying VUS were not correctly diagnosed. Some rare variants of KCNJ11 might contribute to the development of Chinese EOD, although available evidence has not enough power to support them as cause of KCNJ11-MODY. The clinical features of LOF variants were different from GOF variants in KCNJ11-MODY patients. It is necessary to evaluate the pathogenicity of VUS through function experiments.

Rare forms of monogenic diabetes in non-European individuals. First reports of CEL and RFX6 mutations from the Indian subcontinent.

Monogenic diabetes is one of the few examples in metabolic diseases in which a real precision medicine approach can be implemented in daily clinical work. Unfortunately, most of what is known today comes from studies in Whites, thus leaving much uncertainty about the genetics and the clinical presentation of monogenic diabetes in non-Europeans. To fill this gap, we report here two pedigrees from Bangladesh with CEL- and RFX6- diabetes, two rare types of monogenic diabetes which have never been described so far in individuals of the Indian subcontinent. Next generation, Sanger sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA) were performed. Variants' interpretation was according to the American College of Medical Genetics and Genomics guidelines. In the pedigree with CEL-diabetes, a large and never described deletion of exon 2-11 of CEL (confirmed by MLPA) affecting the entire catalytic domain and being likely pathogenic (LP) was observed in both the proband (who had diabetes at 16) and his mother (diabetes at 31), but not in relatives with normoglycemia. In the pedigree with RFX6-diabetes, a LP protein truncation variant (PTV, p.Tyr192*) in RFX6 was found in both the proband (diabetes at 9) and his mother (diabetes at 30), thus suggesting high heterogeneity in disease onset. Normoglycemic relatives were not available for genetic testing. We report genetic features and clinical presentation of the first two cases of CEL- and RFX6-diabetes from the Indian subcontinent, thus contributing to fill the gap of knowledge on monogenic diabetes in non-Europeans.

Molecular pathophysiology of germline mutations in acute myeloid leukemia.

Germline (GL) predisposition to acute myeloid leukemia (AML) has been established as an independent disease entity in the latest World Health Organization classification. Following the American College of Medical Genetics and Genomics guidelines, GL variants were interpreted as causal if they were classified as "pathogenic." GL predisposition can be divided into three groups with different phenotypes, and play an important role in the pathogenesis of adult-onset AML. The clinical course and age of onset of myeloid neoplasms varied considerably for each gene. For example, patients with GATA2 GL variants develop AML before the age of 30 along with bone marrow failure, whereas those with DDX41 GL variants tend to develop AML after the age of 50 without any preceding hematological abnormalities or organ dysfunction. A comprehensive analysis of adult-onset myelodysplastic syndromes in transplant donors showed a 7% frequency of pathogenic GL variants, with DDX41 being the most frequent gene mutation at approximately 3.8%. Future research on GL predisposition at any age of myeloid neoplasm onset will assist in early and accurate diagnosis, development of effective treatment strategies, and selection of suitable donors for stem cell transplantation.

Functional Characterization of ABCA4 Missense Variants Aids Variant Interpretation and Phenotype Prediction in Patients With ABCA4-Retinal Dystrophies.

Biallelic pathogenic variants in the gene encoding the ATP-binding cassette transporter ABCA4 are the leading cause of irreversible vision loss in inherited retinal dystrophies (IRDs). Interpretation of ABCA4 variants is challenging, due to cis-modifying and hypomorphic variants. We have previously detected 10 missense variants of unknown significance (VUS) in patients with suspected ABCA4-retinal dystrophies (ABCA4-RDs) in Norway. In this study, we functionally characterized the VUS to aid interpretation of the variants and to determine if they are associated with the disease. The ABCA4 VUS were expressed in HEK293T cells and the ABCA4 expression level and ATPase activity were determined and correlated with the patients' phenotype. The functional data further used for reclassification of the VUS following the American College of Medical Genetics and Genomics (ACMG) guidelines. Of the 10 VUSs, 2 variants, Cys205Phe and Asn415Thr, were categorized as functionally severe. The age at presentation in the 2 patients carrying these variants was divergent and seemed to be driven by the patients' second pathogenic variants Gly1961Glu and c.5461-10T>C, respectively. Three variants, Val643Gly, Pro799Leu, and Val1433Ile were categorized as functionally moderate, and were found in patients with intermediate/late age at presentation. The remaining five variants were categorized as functionally normal/mild. Based on our data, c.614G>T p.(Cys205Phe), c.1244A>C p.(Asn415Thr), and c.2396C>T p.(Pro799Leu) were reclassified to (likely) pathogenic, while 4 of the functionally normal/mild variants could be reclassified to likely benign. Functional analyses of ABCA4 variants are a helpful tool in variant classification and enable us to better predict the disease severity in patients with ABCA4-RDs.

Clinical analysis of seven cases of primary hyperoxaluria type 1

We retrospectively analyzed the clinical data of seven patients (four men and three women) with primary hyperoxaluria (PH) type 1 (PH1) in the Department of Nephrology of Zhongda Hospital, Southeast University from January 2018 to October 2023. The mean age at disease onset was 32.1 (range: 26-42) years. The mean age at diagnosis was 40.6 (range: 28-51) years. All patients initially had kidney stones, and three patients were found to have renal insufficiency at the time of disease onset. Among them, two patients underwent hemodialysis immediately. Symptoms at the first visit included bone pain (n=7), joint pain or deformity (n=5), fatigue (n=5), hypotension (n=3), and subcutaneous nodules (n=2). Four patients had a family history of PH. All patients had varying degrees of anemia (60-114 g/L), significant hypoalbuminemia (16.5-32.1 g/L), and hypercoagulable state (D-dimer: 2 230-12 781 μg/L). Seven patients received maintenance hemodialysis; their mean age was 37.7 (range: 26-50) years. The mean duration from disease onset to hemodialysis was 5.6 (range: 0-20) years. Five patients repeatedly experienced dialysis access dysfunction. Three patients underwent kidney transplantation before a diagnosis was made, and all transplanted kidneys lost function due to oxalate deposition. The mean follow-up duration was 14.43 (range: 4-38) months. Unfortunately, one patient died. All seven patients underwent computed tomography of the abdomen. All patients suffered skeletal abnormalities, bilateral nephrolithiasis, and nephrocalcinosis. Six patients carried AGXT gene mutations, including four compound heterozygous mutations and two pure homozygous mutations.The mutation sites included: c.823-824dup.AG (p.S275Rfs*38)(exon 8), c.815-816ins.GA (p.S275Rfs*38)(exon 8), c.595G>A (p.G199S) (exon 5), c.32C>G (p.P11R) (exon 1), and c.638C>T (p.A213V)(exon 6). According to the American College of Medical Genetics and Genomics guidelines, two loci were identified as likely pathogenic variants, seven were identified as pathogenic variants, and one locus was identified as having uncertain significance. In addition, patients 1 and 4 underwent skin biopsy, patient 2 underwent renal transplant biopsy, and patient 3 underwent bone marrow biopsy. Interestingly, significant oxalate deposition was found in the tissues. Therefore, PH1 is a rare autosomal recessive inherited disease. This study not only enhanced the understanding of the clinical characteristics of PH1 patients but also had great significance in early diagnosis and treatment of the disease.

Clinical features of a novel compound heterozygous genotype of the BBS2 gene: a case report.

Bardet-Biedl syndrome is a rare autosomal recessive genetic disorder with heterogenous clinical manifestations. The present study reports the clinical features of a novel compound heterozygous genotype of the BBS2 gene in a 14-year-old girl and her 6-year-old sister who had complaints of early-onset low vision. Fundus images revealed retinitis pigmentosa-like changes, and full-field electroretinograms showed no amplitude for the rod or cone response in both patients. Interestingly, nystagmus was observed in the older sister. On physical examination, the sisters had moderate obesity without polydactyly, hypogonadism, or intellectual disability. Exome sequencing revealed a novel compound heterozygous genotype of BBS2 in the sisters, namely the paternally inherited NM_031885.5:c.534 + 1G > T variant and the maternally inherited NM_031885.5:c.700C > T (p.Arg234Ter) variant. Both variants were classified as pathogenic according to the American College of Medical Genetics and Genomics guidelines. This study provides useful information on the genotype-phenotype relationships of the BBS2 gene for genetic counseling and diagnosis.

Beyond the 10%: Unraveling the genetic diversity in Turkish cystic fibrosis patients not eligible for CFTR modulators.

Cystic fibrosis (CF) is an autosomal recessive disease caused by variants of CFTR gene. Over 2000 variants have been identified, and new drugs called CFTR modulators have been developed to target specific defects in the CFTR protein. However, these drugs are only suitable for patients with certain variants of CFTR, and eligibility rates vary depending on race and geographical region. This study aimed to reveal the detailed genotype and clinical characteristics of people with CF (pwCF) at our center in Turkey, a developing country, who are not eligible for CFTR modulators. A total of 445 pwCF followed up at Marmara University were reviewed retrospectively. Variants of the patients ineligible to CFTR modulators were classified based on American College of Medical Genetics guidelines, CFTR classification, the change in the encoded protein, and the variant type. The study revealed that 139 (31.2%) patients weren't eligible for CFTR modulators. There were 60 different variants in the 276 alleles, as two were missing. The majority of patients had missense or nonsense variants, and that the most common variant was c.1545_1546del, which can be said unique to this geography. The study highlights the importance of detecting the variants of ineligible patients in detail to guide future approaches for more targeted and effective interventions in CF care. Testing the effectiveness of CFTR modulators for rare or newly occurring variants is crucial to ensure equal access for pwCF to these therapies from different racial backgrounds and ethnic minorities.