Causative Gene Variants Research Articles

Mosaicism and intronic variants in RB1 gene revealed by next generation sequencing in a cohort of Spanish retinoblastoma patients.

Constitutional variants in the RB1 gene predispose individuals to the development of Retinoblastoma (RB) and the occurrence of second tumors in adulthood. Detection of causal RB1 gene variants is essential to establish the genetic diagnosis and to performing familial studies and counseling. In our cohort of 579 Spanish RB patients, 15% of cases suspected to have a genetic origin remained negative after traditional Sanger sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA) of RB1 gene, likely due to the possibility of mosaicism or non-coding variants. A specific next-generation sequencing (NGS) gene panel was designed to analyze the complete sequence of the RB1 gene. While many familial RB cases showed variants through Sanger and MLPA, the analysis of 65 available sporadic RB patients using the NGS gene panel identified a causative variant in an additional 6 of 26 (23%) bilateral cases and 6 of 39 (15.4%) unilateral cases. Seven of these cases exhibited different degrees of mosaicism (26%, 20%, 15.8%, 8%, 6%, 5.9% and 3%) while 5 cases had heterozygous deep intronic variants, all of them previously described in RB patients. Additional cases with suspected variants, not detected in blood but present in tumor tissue, were also analyzed using NGS PCR amplicons, and mosaicism was confirmed in other 10 sporadic cases. Altogether, the use of NGS increased the diagnostic yield, particularly for patients with sporadic RB in 10 bilateral cases and in 12 unilateral cases.

A single RBM20 missense variant is a potential contributor to dilated cardiomyopathy and/or isolated left ventricular dilatation in the Emilia Romagna region of Italy.

non-syndromic dilated cardiomyopathy (DCM) is found to correlate with a genetic cause in 30-40% of cases. The identification of a causative gene variant can guide treatment options and cascade testing of at-risk family members. Cardiomyopathy multigene panels are routinely used to identify the genetic cause, but often detect variants of uncertain significance (VUS). Pathogenic variants in RBM20 have been reported to account for 2-6% of familial DCM, but geographic differences can be relevant. we collected clinical information, cardiac imaging and family history of 101 individuals with DCM, non-dilated left ventricular cardiomyopathy (NDLVC) and isolated left ventricular dilatation from the Emilia-Romagna Region of Italy. Every subject underwent genetic testing through a next generation sequencing panel of genes related to cardiomyopathies. Analysis of single nucleotide polymorphisms (SNP) was used for haplotype analyses. in our cohort, seven individuals (7%) carried the same heterozygous variant in RBM20 (chr10-110,821,350-G-A; c.2731G>A; p.Val911Met). The referring laboratories reported four further subjects, for a total of 11 unrelated individuals with DCM or isolated left ventricular dilatation from the same geographical area carrying the same variant. These individuals showed high arrhythmic burden and a possible unfavorable evolution towards advanced heart failure. According to guidelines, this variant is classified as VUS; however, its absence in a large local control database and its clinical consistency among affected subjects supports its contributing role. SNP analysis unveiled a common haplotype in the carriers of this variant, suggesting a founder effect. We emphasize the importance of this finding in terms of diagnosis, management and cascade testing of family members.

Whole Exome Sequencing Reveals Candidate Variants in Ion Channel Genes for Pelvic Muscle Dysfunction in Young Females with a Family History.

Pelvic floor dysfunction usually results in pelvic organ prolapse (POP) and/or urinary incontinence. In women, several factors, including pregnancy and vaginal delivery, can affect pelvic muscle conditions. The aim of the study was to perform a genetic analysis in young women with a family history of pelvic floor dysfunction to find potentially harmful variants or variants that increase the risk of developing pelvic floor disorders. We employed whole exome sequencing to test ten young women with pelvic floor muscle dysfunction (along with their parents) and a family history. The average age of symptoms was 29.1 (± 3.98) years old, soon after their first delivery. In five out of ten patients, trio-based WES analysis revealed potentially pathogenic, causative nonsense variants in ion channel genes, including ATP1A4, CLCN1, GRIN2C, and ORAI1, as well as missense variants in PIEZO1 and RYR1. Additionally, some of these patients had variants in genes related to muscle function (MUSK) and connective tissue disorder (FKBP14, p.Glu122ArgfsTer7). The variants found in this study, such as CLCN1 (p.Arg894Ter) and MUSK (p.Val790Met), have already been associated with neuromuscular channelopathy and severe muscle weakness. The identified candidate genes encode mainly proteins involved in electrical action potential and mechanical muscle contraction. The results suggest that the identified genetic variants may result in skeletal muscle ion channelopathies that affect muscle function, gradually leading to muscle hypotonia and weakness.

Variants in theAGBL5 gene are responsible for autosomal recessive Retinitis pigmentosa with hearing loss.

The AGBL5 gene encodes for the Cytoplasmic Carboxypeptidase 5 (CCP5), an α-tubulin deglutamylase that cleaves the γ-carboxyl-linked branching point of glutamylated tubulin. To date, pathogenic variants in AGBL5 have been associated only with isolated retinitis pigmentosa (RP). Hearing loss has not been reported in AGBL5-caused retinal disease. In this study, we performed exome sequencing in probands of eight unrelated families from Italy, Spain, Palestine, Switzerland, and Greece. All subjects had a clinical diagnosis of (suspected) Usher syndrome type II for the concurrent presence of RP and post-verbal sensorineural hearing loss (SNHL) that ranged from mild to moderate.We identified biallelic sequence variants in AGBL5 in all analysed subjects. Four of the identified variants were novel. The variants co-segregated with the retinal and auditory phenotypes in additional affected family members. We did not detect any causative variants in known deafness or Usher syndrome genes that could explain the patients' hearing loss. We therefore conclude that SNHL is a feature of a syndromic presentation of AGBL5 retinopathy. This study provides the first evidence that mutations in AGBL5 can cause syndromic RP forms associated with hearing loss, probably due to dysfunction of sensory cilia in the retina and the inner ear.

Molecular profiles and long-term outcomes of Thai children with hepatic glycogen storage disease in Thailand.

Thus far, genetic analysis of patients clinically diagnosed with glycogen storage diseases (GSDs) in Thailand has not been reported. To evaluate the clinical and biochemical profiles, molecular analysis and long-term outcomes of Thai children diagnosed with hepatic GSD. Children aged < 18 years diagnosed with hepatic GSD and followed up at King Chulalongkorn Memorial Hospital were recruited. Whole-exome sequencing (WES) was performed to identify the causative gene variants. Medical records were assessed. All eight children with histopathologically confirmed diagnosis were classified by WES into subtypes Ia (n = 1), III (n = 3), VI (n = 3), and IX (n = 1). A total number of 10 variants were identified including G6PC (n = 1), AGL (n = 4), PYGL (n = 5), and PHKA2 (n = 1). AGL had two novel variants. The clinical manifestations were hepatomegaly (n = 8), doll-like facies (n = 3), wasting (n = 2), and stunting (n = 5). All patients showed hypoglycemia, transaminitis, and dyslipidemia. The mainstay of treatment was cornstarch supplementation and high-protein and low-lactose-fructose diet. After a median follow-up time of 9.59 years, height turned to normal for age in 3/5 patients and none had malnutrition. Liver enzymes, blood sugar, and lipid profiles improved in all. Hepatomegaly, transaminitis, and hypoglycemia are the hallmarks of GSD confirmed by liver histopathology. Molecular analysis can confirm the diagnosis or classify the subtype that might benefit from personalized treatment, prognosis, and long-term care.

Clinical and genetic characterisation of childhood-onset sensorineural hearing loss reveal associated phenotypes and enrichment of pathogenic founder mutations in the Finnish population

Objective To examine the clinical and genetic characteristics of childhood-onset bilateral sensorineural hearing loss (SNHL) in Finland. Design Retrospective analysis. Study sample A total of 249 children younger than 18 years were diagnosed with bilateral SNHL in Oulu University Hospital, Finland, from 2017 to 2022. Results Pathogenic or likely pathogenic gene variants or chromosome abnormalities explaining SNHL were identified in 41% (N = 101/249) of children. Likely causative variants were more commonly identified in patients with severe SNHL than in those with moderate or mild SNHL. Our study identified likely causative gene variants in 24 different genes and six different likely causative chromosome abnormalities, demonstrating the genetic heterogeneity of SNHL. Population-enriched founder mutations were identified in the CABP2, CLRN1, MYO7A, SUCLA2, TMC1, and TWNK genes. A significant number of patients had associated phenotypes, including global developmental delay or intellectual disability (16%), language disorder (20%), ophthalmological abnormalities (16%), or malformations other than those involving the ear (10%). Conclusions SNHL is genetically and clinically heterogeneous. Pathogenic variants in GJB2 were the most common. Several population-enriched variants were identified as causing SNHL in the northern Finnish population. Associated medical phenotypes are common and should be taken into account in patients’ follow-up and treatment.

Exome variant prioritization in a large cohort of hearing-impaired individuals indicates IKZF2 to be associated with non-syndromic hearing loss and guides future research of unsolved cases

Although more than 140 genes have been associated with non-syndromic hereditary hearing loss (HL), at least half of the cases remain unexplained in medical genetic testing. One reason is that pathogenic variants are located in ‘novel’ deafness genes. A variant prioritization approach was used to identify novel (candidate) genes for HL. Exome-wide sequencing data were assessed for subjects with presumed hereditary HL that remained unexplained in medical genetic testing by gene-panel analysis. Cases in group AD had presumed autosomal dominantly inherited HL (n = 124), and in group AR, presumed autosomal recessive HL (n = 337). Variants in known and candidate deafness genes were prioritized based on allele frequencies and predicted effects. Selected variants were tested for their co-segregation with HL. Two cases were solved by variants in recently identified deafness genes (ABHD12, TRRAP). Variant prioritization also revealed potentially causative variants in candidate genes associated with recessive and X-linked HL. Importantly, missense variants in IKZF2 were found to co-segregate with dominantly inherited non-syndromic HL in three families. These variants specifically affected Zn2+-coordinating cysteine or histidine residues of the zinc finger motifs 2 and 3 of the encoded protein Helios. This finding indicates a complex genotype–phenotype correlation for IKZF2 defects, as this gene was previously associated with non-syndromic dysfunction of the immune system and ICHAD syndrome, including HL. The designed strategy for variant prioritization revealed that IKZF2 variants can underlie non-syndromic HL. The large number of candidate genes for HL and variants therein stress the importance of inclusion of family members for variant prioritization.

Functional characterization of human recessive DIS3 variants in premature ovarian insufficiency†.

Premature ovarian insufficiency (POI) is characterized by the loss or complete absence of ovarian activity in women under the age of 40. Clinical presentation of POI varies with phenotypic severity ranging from premature loss of menses to complete gonadal dysgenesis. POI is genetically heterogeneous with >100 causative gene variants identified thus far. The etiology of POI varies from syndromic, idiopathic, monogenic to autoimmune causes the condition. Genetic diagnoses are beneficial to those impacted by POI as it allows for improved clinical management and fertility preservation. Identifying novel variants in candidate POI genes, however, is insufficient to make clinical diagnoses. The impact of missense variants can be predicted using bioinformatic algorithms but computational approaches have limitations and can generate false positive and false negative predictions. Functional characterization of missense variants, is therefore imperative, particularly for genes lacking a well-established genotype:phenotype correlation. Here we used whole-exome sequencing (WES) to identify the first case of a homozygous missense variant in DIS3 (c.2320C > T; p.His774Tyr) a critical component of the RNA exosome in a POI patient. This adds to the previously described compound heterozygous patient. We perform the first functional characterization of a human POI-associated DIS3 variant. A slight defect in mitotic growth was caused by the variant in a Saccharomyces cerevisiae model. Transgenic rescue of Dis3 knockdown in Drosophila melanogaster with human DIS3 carrying the patient variant led to aberrant ovarian development and egg chamber degeneration. This supports a potential deleterious impact of the human c.2320C > T; p.His774Tyr variant.

HEARRING group genetic marker study: genetic background of CI patients

Background While cochlear implantation (CI) and electric acoustic stimulation (EAS) have a positive outcome in most cases, their effectiveness varies depending on the etiology of the hearing loss. Among the various etiologies, genetic factors are the leading cause of hearing loss and may impact CI and EAS outcomes. Aims/Objectives To reveal the genetic background of the hearing loss in CI/EAS patients in each ethnic population, we undertook a multi-center study involving the genetic testing of hearing loss in CI/EAS patients from 10 centers. Material and Methods Saliva samples and clinical information for the patients and their family members were obtained and next-generation sequencing analysis using a panel carrying 63 deafness genes was then performed. Results Genetic testing successfully identified the causative gene variants in 54.5% (48/88) of patients with pre-lingual onset hearing loss (onset under 6 years) and in 12% (12/95) of those with late-onset hearing loss (onset at 6 years or more). Conclusions and Significance We clearly indicated that genetic factors are the most common cause of hearing loss regardless of ethnic background. Saliva-based genetic testing is a useful tool for multi-center studies seeking to clarify the genetic causes of hearing loss in CI or EAS patients between countries separated by distance.

Heterozygous DSP in-frame deletion in a poodle with syndromic ichthyosis involving additional hair and tooth abnormalities.

Ichthyoses comprise a large heterogeneous group of skin disorders, characterized by generalized scaly and hyperkeratotic skin. We investigated a miniature poodle with early onset generalized scaling, dry and irregularly thickened skin, paw pad hyperkeratosis and abnormalities in hair and teeth. The clinical signs of ichthyosis were confirmed by histopathological examination, which revealed mild epidermal hyperplasia and lamellar orthokeratotic hyperkeratosis. A hereditary condition was suspected and a genetic investigation was initiated. We sequenced the whole genome of the affected dog and searched for potentially causative variants in functional candidate genes for the observed phenotype. The analysis revealed a heterozygous in-frame deletion in DSP, NC_049256.1:g.8804542_8804544del resulting from a de novo mutation event as evidenced by genotyping leukocyte DNA from both parents. The 3 bp deletion is predicted to remove one aspartic acid without disrupting the open reading frame (XM_038584124.1:c.1821_1823del, XP_038440052.1:p.(Asp608del)). The DSP gene encodes desmoplakin, a desmosomal plaque protein, responsible for cell-cell adhesion to provide resistance to mechanical stress in epidermal and cardiac tissues. We hypothesize that the deletion of one amino acid in the N-terminal globular head domain acts in a dominant negative manner and thus impairs the proper connection with other proteins. Several variants in DSP in humans and cattle have been described to result in different phenotypes associated with hair and skin abnormalities, sometimes in combination with variable cardiac and/or dental manifestations. In conclusion, we characterized a new syndromic ichthyosis phenotype in a dog and identified a de novo 3 bp deletion in the DSP gene as causal variant.

Genetic testing and human leukocyte antigen in patients with hypertrophic cardiomyopathy and connective tissue diseases.

Hypertrophic cardiomyopathy (HCM) is caused by myocardial hypertrophy, often due to mutations in cardiac sarcomere protein genes such as beta-myosin heavy chain (MYH7) and myosin-binding protein C (MYBPC3). However, a significant proportion of HCM cases lack identified genetic mutations, and genotype-phenotype correlations remain unclear. Concurrently, potential associations between HCM and human leukocyte antigen (HLA) types, as well as connective tissue diseases, have been proposed. In this single-center study, we aimed to investigate the genetic and HLA profiles of patients with obstructive hypertrophic cardiomyopathy (HOCM) and connective tissue diseases, particularly focusing on the prevalence of genetic variants and HLA types. We conducted a detailed analysis of five patients with HOCM and connective tissue diseases and sarcoidosis, identifying rare variants in causative genes for HCM in two cases and observing specific HLA types that were relatively common. Notably, 15% of all HOCM cases presented with connective tissue diseases, mainly rheumatoid arthritis. These findings underscore the complexity of HCM etiology and suggest potential implications for both diagnostic strategies and therapeutic approaches in patients with concomitant inflammatory conditions.

Anamnestic, clinical, laboratory and molecular genetic characteristics of patients with neonatal diabetes mellitus

BACKGROUND: Currently, there is an increase in the incidence of diabetes mellitus throughout the world, including the steadily increasing number of rare, genetically determined forms of diabetes. Of particular interest are monogenic forms, including neonatal diabetes mellitus, which is a rare heterogeneous disease that manifests, as a rule, in the first 6 months of a child’s life, characterized by a severe labile course and a high risk of complications. Neonatal diabetes mellitus is a rare heterogeneous disease that usually manifests itself in the first 6 months of a child’s life, characterized by a severe, labile course and a high risk of complications. Currently, more than 25 genes are known, mutations in which cause both permanent and transient neonatal diabetes mellitus, as well as syndromic variants of this disease, which are of particular interest due to their severity and polymorphic clinical picture. In this regard, timely verification of the diagnosis is of particular importance. AIM: The aim of this study is to increase the efficiency of diagnosis of neonatal diabetes mellitus based on the analysis of anamnestic, clinical, laboratory and molecular genetic characteristics of patients. MATERIALS AND METHODS: 14 patients with transient and permanent neonatal diabetes mellitus were examined. RESULTS: 11 (78.6%) patients had isolated neonatal diabetes, in three of them the disease was verified in the structure of hereditary syndromes (Wolcott–Rallison syndrome, IPEX syndrome and Donohue syndrome). According to molecular genetic analysis, 14 variants were found in the genes ABCC8, KCNJ11, GCK, GATA6, WFS1, CACNA1D, EIF2AK3, FOXP3, PAX4, INSR, IGF1R, three of which were not previously described in the literature. CONCLUSIONS: The clinical heterogeneity identified in patients is determined primarily by the diversity of verified variants in causative genes. New variants in the CACNA1D and IGF1R genes that may be associated with the development of NDM, remain poorly understood and require further research.

Colorectal cancer and advanced adenoma characteristics according to causative mismatch repair gene variant in Japanese colorectal surveillance for Lynch syndrome.

The optimal interval of colonoscopy (CS) surveillance in cases with Lynch syndrome (LS), and stratification according to the causative mismatch repair gene mutation, has received much attention. To verify a feasible and effective CS surveillance strategy, we investigated the colorectal cancer (CRC) incidence at different intervals and the characteristics of precancerous colorectal lesions of LS cases. This retrospective multicenter study was conducted in Japan. CRCs and advanced adenomas (AAs) in 316 LS cases with germline pathogenic variants (path_) were analyzed according to the data of 1,756 registered CS. The mean time interval for advanced CRCs (ACs) detected via CS surveillance was 28.7months (95% confidence interval: 13.8-43.5). The rate of AC detection within (2.1%) and beyond 2years (8.7%) differed significantly (p = 0.0003). AAs accounted for 43%, 46%, and 41% of lesions < 10mm in size in the MLH1-, MSH2-, and MSH6-groups, respectively. The lifetime incidence of metachronous CRCs requiring intestinal resection for path_MLH1, path_MSH2, and path_MSH6 cases was 34%, 23%, and 14% in these cases, respectively. The cumulative CRC incidence showed a trend towards a 10-year delay for path_MSH6 cases as compared with that for path_MLH1 and path_MSH2 cases. In cases with path_MLH1, path_MSH2, and path_MSH6, maintaining an appropriate CS surveillance interval of within 2years is advisable to detect of the colorectal lesion amenable to endoscopic treatment. path_MSH6 cases could be stratified with path_MLH1 and MSH2 cases in terms of risk of metachronous CRC and age of onset.

Etiology of combined pituitary hormone deficiency: GNAO1 as a novel candidate gene.

Because the causes of combined pituitary hormone deficiency (CPHD) are complex, the etiology of congenital CPHD remains unknown in most cases. The aim of the study was to identify the genetic etiology of CPHD in a well-defined single-center cohort. In total, 34 children (12 girls) with congenital CPHD (growth hormone (GH) deficiency and impaired secretion of at least one other pituitary hormone) treated with GH in our center were enrolled in the study. Their median age was 11.2 years, pre-treatment height was -3.2 s.d., and maximal stimulated GH was 1.4 ug/L. Of them, 30 had central adrenal insufficiency, 27 had central hypothyroidism, ten had hypogonadotropic hypogonadism, and three had central diabetes insipidus. Twenty-six children had a midline defect on MRI. Children with clinical suspicion of a specific genetic disorder underwent genetic examination of the gene(s) of interest via Sanger sequencing or array comparative genomic hybridization. Children without a detected causal variant after the first-tier testing or with no suspicion of a specific genetic disorder were subsequently examined using next-generation sequencing growth panel. Variants were evaluated by the American College of Medical Genetics standards. Genetic etiology was confirmed in 7/34 (21%) children. Chromosomal aberrations were found in one child (14q microdeletion involving the OTX2 gene). The remaining 6 children had causative genetic variants in the GLI2, PROP1, POU1F1, TBX3, PMM2, and GNAO1 genes, respectively. We elucidated the cause of CPHD in a fifth of the patients. Moreover, our study supports the PMM2 gene as a candidate gene for CPHD and suggests pathogenic variants in the GNAO1 gene as a potential novel genetic cause of CPHD.

Breast Cancer is Increased in Women with Primary Ovarian Insufficiency.

DNA damage/repair gene variants are associated with both primary ovarian insufficiency (POI) and cancer risk. We hypothesized that a subset of women with POI and family members would have increased risk for cancer. Case-control population-based study using records from 1995-2022. Two major Utah academic healthcare systems serving 85% of the state. Women with POI (n=613) were identified using ICD codes and reviewed for accuracy. Relatives were linked using the Utah Population Database. Cancer diagnoses were identified using the Utah Cancer Registry. The relative risk of cancer in women with POI and relatives was estimated by comparison to population rates. Whole genome sequencing was performed on a subset of women. Breast cancer was increased in women with POI (OR [95%CI] 2.20 [1.30, 3.47]; p=0.0023) and there was a nominally significant increase in ovarian cancer. Probands with POI were 36.5±4.3 years and 59.5±12.7 years when diagnosed with POI and cancer, respectively. Causal and candidate gene variants for cancer and POI were identified.Among second-degree relatives of these women, there was an increased risk of breast (1.28 [1.08, 1.52]; p=0.0078) and colon cancer (1.50 [1.14, 1.94]; p=0.0036). Prostate cancer was increased in first- (1.64 [1.18, 2.23]; p=0.0026), second- (1.54 [1.32, 1.79]; p<0.001), and third-degree relatives (1.33 [1.20, 1.48]; p<0.001). Data suggest common genetic risk for POI and reproductive cancers. Tools are needed to predict cancer risk in women with POI and potentially to counsel about risks of hormone replacement therapy.

Cerebellar atrophy in genetic epileptic encephalopathies: A cohort study and a systematic review

To analyze cerebellar atrophy in genetic epileptic encephalopathies (EEs). This research included a retrospective cohort study conducted from January 2016 to December 2023 and a systematic review on cerebellar atrophy in genetic EEs. Pediatric individuals who were diagnosed with EEs based on electroclinical features, carried causative gene variants, and exhibited cerebellar atrophy were recruited. Electroclinical features, neuroimaging findings, and causative variants of eligible individuals were analyzed. The cohort study showed 10 of 67 pediatric individuals (10/67; 15 %) who were diagnosed with genetic EEs had cerebellar atrophy; and 6 of the 10 individuals (6/10; 60 %) exhibited cerebellar signs. Diagnostic delay between the detection of cerebellar atrophy and the identification of genetic diagnosis existed in 6 individuals (6/10; 60 %) and the median duration was 4.4 years. A total of 32 genes, including 31 genes from the literature review and a newly identified SCN2A gene in this cohort, were reported associated with cerebellar atrophy in genetic EEs. Twenty-six genes (26/32; 81 %) accounted for cerebellar atrophy associated with other brain anomalies and 6 genes (6/32; 19 %) caused isolated cerebellar atrophy. Twenty-five genes (25/32; 78 %) showed late-onset cerebellar atrophy identified after the age of 1 year old. Cerebellar atrophy is not uncommon in genetic EEs and may serve as an indicator for molecular diagnosis in clinical practice. To shorten the diagnostic delay, follow-up neuroimaging study is crucial because of high rate of clinico-radiological dissociation and late-onset cerebellar atrophy in this patient group.

GENETIC ETIOLOGY AND CLINICAL FEATURES OF ACHROMATOPSIA IN JAPAN.

To ascertain the characteristics of achromatopsia (ACHM) in Japan by analyzing the genetic and phenotypic features of patients with ACHM. The medical records of 52 patients from 47 Japanese families who were clinically diagnosed with ACHM were reviewed in this retrospective observational study. Thirty-six causative variants of ACHM were identified in 26 families via whole-exome sequencing: PDE6C (12 families), CNGA3 (10 families), CNGB3 (two families), and GNAT2 (two families). However, none of the 6 causative variants that are known to cause ACHM, or the 275 other genes listed in RetNet, were observed in 19 families. A significant trend toward older age and worsening of ellipsoid zone disruption on optical coherence tomography images was observed (P < 0.01). Progressive ellipsoid zone disruptions were observed in 13 eyes of seven patients during the follow-up visits. These patients harbored one or more variants in PDE6C. The ACHM phenotype observed in this study was similar to those observed in previous reports; however, the causative gene variants differed from those in Europe. The low identification ratio of causative genes in whole-exome sequencing suggests the presence of unique hotspots in Japanese patients with ACHM that were not detectable via ordinal whole-exome sequencing.

Impact of 12-SNP and 6-SNP Polygenic Scores on Predisposition to High LDL-Cholesterol Levels in Patients with Familial Hypercholesterolemia.

Familial hypercholesterolemia (FH) comprises high LDL-cholesterol (LDL-c) levels and high cardiovascular disease risk. In the absence of pathogenic variants in causative genes, a polygenic basis was hypothesized. In a population of 418 patients (excluding homozygotes) with clinical suspicion of FH, the FH-causative genes and the regions of single nucleotide polymorphisms (SNPs) included in 12-SNP and 6-SNP scores were sequenced by next-generation sequencing, allowing for the detection of pathogenic variants (V+) in 220 patients. To make a comparison, only patients without uncertain significance variants (V-/USV-) were considered (n = 162). Higher values of both scores were observed in V+ than in V-. Considering a cut-off leading to 80% of V-/USV- as score-positive, a lower prevalence of patients positive for both 12-SNP and 6-SNP scores was observed in V+ (p = 0.010 and 0.033, respectively). Mainly for the 12-SNP score, among V+ patients, higher LDL-c levels were observed in score-positive (223 mg/dL -IQR 187-279) than in negative patients (212 mg/dL -IQR 162-240; p = 0.006). Multivariate analysis confirmed the association of scores and LDL-c levels independently of age, sex, and presence of pathogenic variants and revealed a greater association in children. The 12-SNP and 6-SNP polygenic scores could explain hypercholesterolemia in patients without pathogenic variants as well as the variability of LDL-c levels among patients with FH-causative variants.

Review of childhood genetic nephrolithiasis and nephrocalcinosis.

Nephrolithiasis (NL) is a common condition worldwide. The incidence of NL and nephrocalcinosis (NC) has been increasing, along with their associated morbidity and economic burden. The etiology of NL and NC is multifactorial and includes both environmental components and genetic components, with multiple studies showing high heritability. Causative gene variants have been detected in up to 32% of children with NL and NC. Children with NL and NC are genotypically heterogenous, but often phenotypically relatively homogenous, and there are subsequently little data on the predictors of genetic childhood NL and NC. Most genetic diseases associated with NL and NC are secondary to hypercalciuria, including those secondary to hypercalcemia, renal phosphate wasting, renal magnesium wasting, distal renal tubular acidosis (RTA), proximal tubulopathies, mixed or variable tubulopathies, Bartter syndrome, hyperaldosteronism and pseudohyperaldosteronism, and hyperparathyroidism and hypoparathyroidism. The remaining minority of genetic diseases associated with NL and NC are secondary to hyperoxaluria, cystinuria, hyperuricosuria, xanthinuria, other metabolic disorders, and multifactorial etiologies. Genome-wide association studies (GWAS) in adults have identified multiple polygenic traits associated with NL and NC, often involving genes that are involved in calcium, phosphorus, magnesium, and vitamin D homeostasis. Compared to adults, there is a relative paucity of studies in children with NL and NC. This review aims to focus on the genetic component of NL and NC in children.

Idiopathic generalized epilepsy in a family with SCN4A-related myotonia.

Myotonia is a clinical sign typical of a group of skeletal muscle channelopathies, the non-dystrophic myotonias. These disorders are electrophysiologically characterized by altered membrane excitability, due to specific genetic variants in known causative genes (CLCN1 and SCN4A). Juvenile Myoclonic Epilepsy (JME) is an epileptic syndrome identified as idiopathic generalized epilepsy, its genetics is complex and still unclarified. The co-occurrence of these two phenotypes is rare and the causes likely have a genetic background. In this study, we have genetically investigated an Italian family in which co-segregates myotonia, JME, or abnormal EEG without seizures was observed. All six individuals of the family, 4 affected and 2 unaffected, were clinically evaluated; EMG and EEG examinations were performed. For genetic testing, Exome Sequencing was performed for the six family members and Sanger sequencing was used to confirm the candidate variant. Four family members, the mother and three siblings, were affected by myotonia. Moreover, EEG recordings revealed interictal generalized sharp-wave discharges in all affected individuals, and two siblings were affected by JME. All four affected members share the same identified variant, c.644 T > C, p.Ile215Thr, in SCN4A gene. Variants that could account for the epileptic phenotype alone, separately from the myotonic one, were not identified. These results provide supporting evidence that both myotonic and epileptic phenotypes could share a common genetic background, due to variants in SCN4A gene. SCN4A pathogenic variants, already known to be causative of myotonia, likely increase the susceptibility to epilepsy in our family. This study analyzed all members of an Italian family, in which the mother and three siblings had myotonia and epilepsy. Genetic analysis allowed to identify a variant in the SCN4A gene, which appears to be the cause of both clinical signs in this family.