Most arteriovenous malformations (AVMs) are localized and occur sporadically. However, they also can be multifocal in autosomal-dominant disorders, such as hereditary hemorrhagic telangiectasia and ...capillary malformation (CM)-AVM. Previously, we identified
mutations in 50% of patients with CM-AVM. Herein we studied non-RASA1 patients to further elucidate the pathogenicity of CMs and AVMs.
We conducted a genome-wide linkage study on a CM-AVM family. Whole-exome sequencing was also performed on 9 unrelated CM-AVM families. We identified a candidate gene and screened it in a large series of patients. The influence of several missense variants on protein function was also studied in vitro.
We found evidence for linkage in 2 loci. Whole-exome sequencing data unraveled 4 distinct damaging variants in
in 5 families that cosegregated with CM-AVM. Overall, screening of
detected 47 distinct mutations in 54 index patients: 27 led to a premature stop codon or splice-site alteration, suggesting loss of function. The other 20 are nonsynonymous variants that result in amino acid substitutions. In vitro expression of several mutations confirmed loss of function of EPHB4. The clinical features included multifocal CMs, telangiectasias, and AVMs.
We found
mutations in patients with multifocal CMs associated with AVMs. The phenotype, CM-AVM2, mimics
-related CM-AVM1 and also hereditary hemorrhagic telangiectasia.
-encoded p120RASGAP is a direct effector of EPHB4. Our data highlight the pathogenetic importance of this interaction and indicts EPHB4-RAS-ERK signaling pathway as a major cause for AVMs.
Our comprehensive cohort of 1100 unrelated achromatopsia (ACHM) patients comprises a considerable number of cases (~5%) harboring only a single pathogenic variant in the major ACHM gene CNGB3. We ...sequenced the entire CNGB3 locus in 33 of these patients to find a second variant which eventually explained the patients’ phenotype. Forty‐seven intronic CNGB3 variants were identified in 28 subjects after a filtering step based on frequency and the exclusion of variants found in cis with pathogenic alleles. In a second step, in silico prediction tools were used to filter out those variants with little odds of being deleterious. This left three variants that were analyzed using heterologous splicing assays. Variant c.1663–1205G>A, found in 14 subjects, and variant c.1663‐2137C>T, found in two subjects, were indeed shown to exert a splicing defect by causing pseudoexon insertion into the transcript. Subsequent screening of further unsolved CNGB3 subjects identified four additional cases harboring the c.1663–1205G>A variant which makes it the eighth most frequent CNGB3 variant in our cohort. Compound heterozygosity could be validated in ten cases. Our study demonstrates that whole gene sequencing can be a powerful approach to identify the second pathogenic allele in patients apparently harboring only one disease‐causing variant.
The lipid molecule ceramide is transported from the endoplasmic reticulum to the Golgi apparatus for sphingomyelin production via the ceramide transport protein (CERT), encoded by CERT1. ...Hyperphosphorylation of CERT’s serine-repeat motif (SRM) decreases its functionality. Some forms of inherited intellectual disability (ID) have been associated with a serine-to-leucine substitution in the SRM (S132L mutation) and a glycine-to-arginine substitution outside the SRM (G243R mutation) in CERT; however, it is unclear if mutations outside the SRM disrupt the control of CERT functionality. In the current investigation, we identified a new CERT1 variant (dupAA) in a patient with mild ID that resulted from a frameshift at the C-terminus of CERT1. However, familial analysis revealed that the dupAA variant was not associated with ID, allowing us to utilize it as a disease-matched negative control for CERT1 variants that are associated with ID. Biochemical analysis showed that G243R and S132L, but not dupAA, impair SRM hyperphosphorylation and render the CERT variants excessively active. Additionally, both S132L and G243R mutations but not dupAA caused the proteins to be distributed in a punctate subcellular manner. On the basis of these findings, we infer that the majority of ID-associated CERT variants may impair SRM phosphorylation-dependent repression, resulting in an increase in sphingomyelin production concurrent with CERT subcellular redistribution.
The number of genes implicated in neurodevelopmental conditions is rapidly growing. Recently, variants in PPP2R1A have been associated with syndromic intellectual disability and a consistent, but ...still expanding, phenotype. The PPP2R1A gene encodes a protein subunit of the serine/threonine protein phosphatase 2A enzyme, which plays a critical role in cellular function. We report an individual showing pontocerebellar hypoplasia (PCH), microcephaly, optic and peripheral nerve abnormalities, and an absence of typical features like epilepsy and an abnormal corpus callosum. He bears an unreported variant in an atypical region of PPP2R1A. In silico studies, functional analysis using immunofluorescence, and super-resolution microscopy techniques were performed to investigate the pathogenicity of the variant. This analysis involved a comparative analysis of the patient’s fibroblasts with both healthy control cells and cells from an individual with the previously described phenotype. The results showed reduced expression of PPP2R1A and the presence of aberrant protein aggregates in the patient’s fibroblasts, supporting the pathogenicity of the variant. These findings suggest a potential association between PPP2R1A variants and PCH, expanding the clinical spectrum of PPP2R1A-related neurodevelopmental disorder. Further studies and descriptions of additional patients are needed to fully understand the genotype–phenotype correlation and the underlying mechanisms of this novel phenotype.
Mutations in CYP4F22 cause autosomal recessive congenital ichthyosis (ARCI). However, less than 10% of all ARCI patients carry a mutation in CYP4F22. In order to identify the molecular basis of ARCI ...among our patients (a cohort of ninety-two Spanish individuals) we performed a mutational analysis using direct Sanger sequencing in combination with a multigene targeted NGS panel. From these, eight ARCI families (three of them with Moroccan origin) were found to carry five different CYP4F22 mutations, of which two were novel. Computational analysis showed that the mutations found were present in highly conserved residues of the protein and may affect its structure and function. Seven of the eight families were carriers of a highly recurrent CYP4F22 variant, c.1303C>T; p.(His435Tyr). A 12Mb haplotype was reconstructed in all c.1303C>T carriers by genotyping ten microsatellite markers flanking the CYP4F22 gene. A prevalent 2.52Mb haplotype was observed among Spanish carrier patients suggesting a recent common ancestor. A smaller core haplotype of 1.2Mb was shared by Spanish and Moroccan families. Different approaches were applied to estimate the time to the most recent common ancestor (TMRCA) of carrier patients with Spanish origin. The age of the mutation was calculated by using DMLE and BDMC2. The algorithms estimated that the c.1303C>T variant arose approximately 2925 to 4925 years ago, while Spanish carrier families derived from a common ancestor who lived in the XIII century. The present study reports five CYP4F22 mutations, two of them novel, increasing the number of CYP4F22 mutations currently listed. Additionally, our results suggest that the recurrent c.1303C>T change has a founder effect in Spanish population and c.1303C>T carrier families originated from a single ancestor with probable African ancestry.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
OBJECTIVE:Describe the incidence of cancer in a large cohort of patients with myotonic dystrophy type 1 (DM1) and to unravel the underlying molecular mechanisms.
METHODS:Standardized incidence ratios ...(SIRs) were calculated in the Gipuzkoa DM1 cohort (1985–2013), dividing observed numbers by expected numbers for all cancers combined and stratified by sex. An estimation of the expected incidence was achieved by multiplying the age- and sex-specific incidence rates from the Basque population cancer registry by the person-years observed in the study cohort. Large-scale gene expression of peripheral blood mononuclear cell samples derived from 10 individuals with DM1 (5 men, 5 women) and 10 healthy matched controls was analyzed by the Human Gene 1.0 ST Affymetrix microarray.
RESULTS:During 18,796 person-years of follow-up, corresponding to 424 patients with DM1, we observed 70 cancers in 62 patients giving a 1.81-fold risk (95% confidence interval CI 1.37–2.36), which was stronger in women than in men. Ovary (SIR 8.33, 95% CI 1.72–24.31) and endometrium (SIR 6.86, 95% CI 2.23–16.02) in women and thyroid (SIR 23.33, 95% CI 9.38–48.08) and brain (SIR 9.80, 95% CI 3.18–22.88) in both sexes were tumor sites with significantly higher risks in DM1. There were differences in gene expression between healthy controls and patients with DM1 and between men and women with DM1; all patients with DM1 combined and female patients with DM1 displayed significant downregulation of the microRNA (miRNA)-200c/141 tumor suppressor family.
CONCLUSIONS:Oncologic risk is increased in DM1, especially in women and for gynecologic, brain, and thyroid cancer. Expression of the miRNA-200/miRNA-141 tumor suppressor family is decreased in women with DM1.
Despite the growing interest and the potential benefits of idebenone as a repurposed drug for different orphan conditions, data regarding its monitoring are scarce. Our main goal was to report plasma ...idebenone values in a cohort of Friedreich’s ataxia (FRDA) patients during a long-term follow-up. Taking advantage of this, we also assessed cardiological and neurological status together with idebenone values and genetic background.
Long-term follow-up retrospective study in 27 FRDA patients with a disease onset at the paediatric age treated with idebenone by compassionate use. Plasma idebenone was measured by HPLC with electrochemical detection.
Median plasma idebenone values increased when doses were increased, but apparently linearity was lost in the highest dose group. Marked intraindividual and interindividual differences were observed among patients. We did not find a consistent positive effect after analysis of paired data at the beginning and the end of the study. We only found a correlation between some cardiological measures and the duration of idebenone therapy at high doses, but with uncertain significance.
The large variations observed among the different individuals involved in this study should be considered for optimization of individual dosage regimens.
•Despite the growing interest and the potential benefits of idebenone, data regarding its monitoring are scarce.•We report plasma idebenone values of a cohort of 27 Friedreich’s ataxia patients during a long-term follow-up period.•Large interindividual and intraindividual variability in plasma idebenone concentrations was observed.•These large variations should be considered for optimization of individual dosage regimens.
Pseudohypoaldosteronism (PHA) comprises a diverse group of rare diseases characterized by sodium and potassium imbalances incorrectly attributed to a defect in aldosterone production. Two different ...forms of PHA have been described, type I (PHAI) and type II (PHAII). PHAI has been subclassified into renal and systemic. Given the rarity and heterogeneity of this group of disorders we report three patients who carry PHA and a brief revision of current literature focused on the comparative analysis of PHAI and PHAII. Cases 1 and 2 presented with hyponatremia, hyperkalemia, metabolic acidosis and elevated plasma aldosterone and plasma renin activity in the neonatal period. Sequence analysis of the
gene demonstrated a novel heterozygous c.403C>T mutation in case 1 and a complete deletion in case 2, confirming the diagnosis of renal PHAI. Case 3 was a 4-year-old with hypertension, hyperkalemia, metabolic acidosis, normal plasma aldosterone and decreased plasma renin activity. Sequence analysis of the
gene demonstrated a previously unreported heterozygous c.1377+2T>3 mutation, confirming the diagnosis of PHAII-E. We highlight the importance of the determination of plasma aldosterone and plasma renin activity in the context of persistent sodium and potassium imbalances in children.
Okur‐Chung neurodevelopmental syndrome (OCNS, MIM#617062) is a rare autosomal dominant syndrome related to CSNK2A1 mutations. It is characterized by intellectual disability, hypotonia, feeding and ...speech difficulties, dysmorphic features, and multisystem involvement. To date, less than 30 patients with OCNS have been described in detail in the literature, primarily in Asian populations. Here, we report a 5‐year‐old Spanish female with OCNS arising from a novel CSNK2A1 mutation c.149A>G, p.Tyr50Cys. Although her clinical features were compatible with OCNS syndrome, magnetic resonance imaging unexpectedly showed a duplication of the pituitary gland, a clinical finding not previously related to any known genetic condition. Other novel signs were an absence of the olfactory bulbs and multiple duplications of cervical vertebrae. We suggest that the midline abnormalities may be a significant part of this condition and lead to diagnostic suspicion. However, further descriptions are needed.
Myotonic dystrophy type 1 (DM1), also known as Steinert's disease, is a chronic, progressive and disabling multisystemic disorder with a broad spectrum of severity that arises from an ...autosomal-dominant expansion of the Cytosine-Thymine-Guanine (CTG) triplet repeat in the 3' untranslated region of the
gene (19q13.3).
In this study, we report the case of a family with several intergenerational expansions of the CTG repeat, with an additional case of a false suspicion of contraction phenomenon due to TP-PCR limitations.
The meiotic instability of the (CTG)
repeats leads to genetic anticipation where increased size of DM1 mutation and a more severe phenotype have been reported in affected individuals across generations. Even if extremely rare, a decrease in the CTG repeat size during transmission from parents to child can also occur, most frequently during paternal transmissions.
PDF
