Intrafamilial Phenotype Variability in Two Male Siblings, With X-linked Juvenile Retinoschisis and Dorzolamide Treatment Effect in the Natural History of the Disease

To investigate how genotype is related to phenotype and document correlations of genotype-phenotype with response of topical administration of dorzolamide in siblings affected with X-linked juvenile retinoschisis (XLRS). We performed a retrospective study on two male siblings (four eyes) with XLRS, who were treated with topical installation of dorzolamide. Clinical diagnosis was supported with familial genetic analysis with bi-directional Sanger sequencing of RS1 pathogenic variant. Optical coherence tomography (OCT), fundus fluorescein angiography (FFA), ultrasound scan (U/S) and electroretinogram (ERG) were used in the evaluation. Central macular thickness (CMT) and best corrected visual acuity (BCVA) were recorded monthly for eighteen months. We performed genetic analysis in their family for mutations in the gene that encodes the protein retinoschisin, responsible for retinoschisis (RS1).  It was proved that phenotype variability might be related to the same pathogenic variant. While there was an improvement in BCVA and OCT central macular thickness in the patient with the mild form of disease, the visual acuity and the OCT scans of the patient with severe form of disease did not improve. Intrafamilial phenotypic variability between individuals sharing identical pathogenic variant was documented. Both our patients had a pathogenic variant in a hemizygous state at a genomic location in exon 6 of the RS1 gene; Frameshift mutation that is likely to cause protein truncation was identified which is suggested to result in greater clinical severity. Consequently, it was found that response to dorzolamide is correlated to phenotypic severity

Intrafamilial Phenotype Variability in Two Male Siblings, With X-linked Juvenile Retinoschisis and Dorzolamide Treatment Effect in the Natural History of the Disease

To investigate how genotype is related to phenotype and document correlations of genotype-phenotype with response of topical administration of dorzolamide in siblings affected with X-linked juvenile retinoschisis (XLRS). We performed a retrospective study on two male siblings (four eyes) with XLRS, who were treated with topical installation of dorzolamide. Clinical diagnosis was supported with familial genetic analysis with bi-directional Sanger sequencing of RS1 pathogenic variant. Optical coherence tomography (OCT), fundus fluorescein angiography (FFA), ultrasound scan (U/S) and electroretinogram (ERG) were used in the evaluation. Central macular thickness (CMT) and best corrected visual acuity (BCVA) were recorded monthly for eighteen months. We performed genetic analysis in their family for mutations in the gene that encodes the protein retinoschisin, responsible for retinoschisis (RS1).  It was proved that phenotype variability might be related to the same pathogenic variant. While there was an improvement in BCVA and OCT central macular thickness in the patient with the mild form of disease, the visual acuity and the OCT scans of the patient with severe form of disease did not improve. Intrafamilial phenotypic variability between individuals sharing identical pathogenic variant was documented. Both our patients had a pathogenic variant in a hemizygous state at a genomic location in exon 6 of the RS1 gene; Frameshift mutation that is likely to cause protein truncation was identified which is suggested to result in greater clinical severity. Consequently, it was found that response to dorzolamide is correlated to phenotypic severity

Mild Phenotype in a Patient with a De Novo

We report on a 29-year-old Greek-Cypriot female with a de novo 6.3 Mb distal 10q26.2q26.3 deletion. She had a very mild neurocognitive phenotype with near normal development and intellect. In addition, she had certain distinctive features and postural orthostatic tachycardia. We review the relevant literature and postulate that certain of her features can be diagnostically relevant. This report illustrates the powerful diagnostic ability of array-CGH in the elucidation of relatively mild phenotypes

Can cutaneous telangiectasiae as late normal-tissue injury predict cardiovascular disease in women receiving radiotherapy for breast cancer?

Background: Overall, ~5% of patients show late normal-tissue damage after radiotherapy with a smaller number having a risk of radiation-induced heart disease. Although the data are conflicting, large studies have shown increased risks of cardiovascular disease (CVD) for irradiated patients compared with non-irradiated ones, or for those treated to the left breast or chest wall compared with those treated to the right. Cutaneous telangiectasiae as late normal-tissue injury have so far only been regarded as a cosmetic burden. Methods: The relationship between late normal-tissue radiation injury phenotypes in 149 irradiated breast cancer patients and the presence of cardiovascular disease were examined. Results: A statistically significant association between the presence of skin telangiectasiae and the long-term risk of CVD was shown in these patients (P=0.017; Fisher's exact test). Interpretation: This association may represent initial evidence that telangiectasiae can be used as a marker of future radiation-induced cardiac complications. It could also suggest a common biological pathway for the development of both telangiectasiae and CVD on the basis of a genetically predisposed endothelium. To our knowledge this is the first reported study looking at this association

Spinal muscular atrophy type I associated with a novel SMN1 splicing variant that disrupts the expression of the functional transcript

IntroductionSpinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by pathogenic variants in the SMN1 gene. The majority of SMA patients harbor a homozygous deletion of SMN1 exon 7 (95%). Heterozygosity for a conventional variant and a deletion is rare (5%) and not easily detected, due to the highly homologous SMN2 gene interference. SMN2 mainly produces a truncated non-functional protein (SMN-d7) instead of the full-length functional (SMN-FL). We hereby report a novel SMN1 splicing variant in an infant with severe SMA.MethodsMLPA was used for SMN1/2 exon dosage determination. Sanger sequencing approaches and long-range PCR were employed to search for an SMN1 variant. Conventional and improved Real-time PCR assays were developed for the qualitative and quantitative SMN1/2 RNA analysis.ResultsThe novel SMN1 splice-site variant c.835-8_835-5delinsG, was identified in compound heterozygosity with SMN1 exons 7/8 deletion. RNA studies revealed complete absence of SMN1 exon 7, thus confirming a disruptive effect of the variant on SMN1 splicing. No expression of the functional SMN1-FL transcript, remarkable expression of the SMN1-d7 and increased levels of the SMN2-FL/SMN2-d7 transcripts were observed.DiscussionWe verified the occurrence of a non-deletion SMN1 variant and supported its pathogenicity, thus expanding the SMN1 variants spectrum. We discuss the updated SMA genetic findings in the Cypriot population, highlighting an increased percentage of intragenic variants compared to other populations

The pathogenic p.Gln319Ter variant is not causing congenital adrenal hyperplasia when inherited in one of the duplicated CYP21A2 genes

ObjectiveThe study aimed to identify the pathogenic status of p.Gln319Ter (NM_000500.7: c.955C>T) variant when inherited in a single CYP21A2 gene (bimodular RCCX haplotype) and to discriminate between a non-causing congenital adrenal hyperplasia (CAH) allele when inherited in a duplicated and functional CYP21A2 gene context (trimodular RCCX haplotype).Methods38 females and 8 males with hyperandrogenemia, previously screened by sequencing and identified as carriers for the pathogenic p.Gln319Ter, were herein tested by multiplex ligation-dependent probe amplification (MLPA) and a real-time PCR Copy number Variation (CNV) assay.ResultsBoth MLPA and real-time PCR CNV analyses confirmed a bimodular and pathogenic RCCX haplotype with a single CYP21A2 in 19/46 (41.30%) p.Gln319Ter carriers and who in parallel all shared elevated 17-OHP levels. The remaining 27 individuals that also carried the p.Gln319Ter exhibited low 17-OHP levels as a result of their carriership of a duplicated CYP21A2 with a trimodular RCCX haplotype. Interestingly, all of these individuals also carried in linkage disequilibrium with p.Gln319Ter two single nucleotide polymorphisms, the c.293-79G>A (rs114414746) in intron 2 and the c.*12C>T (rs150697472) in the 3’-UTR. Therefore, these variants can be used to distinguish between pathogenic and non-pathogenic genomic contexts of the c.955T (p.Gln319) in the genetic diagnosis of congenital adrenal hyperplasia (CAH).ConclusionThe employed methodologies identified a considerable number of individuals with non-pathogenic p.Gln319Ter from the individuals that typically carry the pathogenic p.Gln319Ter in a single CYP21A2. Therefore, it is extremely important the detection of such haplotypes for the prenatal diagnosis, treatment and genetic counseling in patients with CAH

Goldberg-Shprintzen syndrome is determined by the absence, or reduced expression levels, of KIFBP.

Goldberg-Shprintzen syndrome (GOSHS) is caused by loss of function variants in the kinesin binding protein gene (KIFBP). However, the phenotypic range of this syndrome is wide, indicating that other factors may play a role. To date, 37 patients with GOSHS have been reported. Here, we document nine new patients with variants in KIFBP: seven with nonsense variants and two with missense variants. To our knowledge, this is the first time that missense variants have been reported in GOSHS. We functionally investigated the effect of the variants identified, in an attempt to find a genotype-phenotype correlation. We also determined whether common Hirschsprung disease (HSCR)-associated single nucleotide polymorphisms (SNPs), could explain the presence of HSCR in GOSHS. Our results showed that the missense variants led to reduced expression of KIFBP, while the truncating variants resulted in lack of protein. However, no correlation was found between the severity of GOSHS and the location of the variants. We were also unable to find a correlation between common HSCR-associated SNPs, and HSCR development in GOSHS. In conclusion, we show that reduced, as well as lack of KIFBP expression can lead to GOSHS, and our results suggest that a threshold expression of KIFBP may modulate phenotypic variability of the disease

European lipodystrophy registry: Background and structure

Background: Lipodystrophy syndromes comprise a group of extremely rare and heterogeneous diseases characterized by a selective loss of adipose tissue in the absence of nutritional deprivation or catabolic state. Because of the rarity of each lipodystrophy subform, research in this area is difficult and international co-operation mandatory. Therefore, in 2016, the European Consortium of Lipodystrophies (ECLip) decided to create a registry for patients with lipodystrophy. Results: The registry was build using the information technology Open Source Registry System for Rare Diseases in the EU (OSSE), an open-source software and toolbox. Lipodystrophy specific data forms were developed based on current knowledge of typical signs and symptoms of lipodystrophy. The platform complies with the new General Data Protection Regulation (EU) 2016/679 by ensuring patient pseudonymization, informational separation of powers, secure data storage and security of communication, user authentication, person specific access to data, and recording of access granted to any data. Inclusion criteria are all patients with any form of lipodystrophy (with the exception of HIV-associated lipodystrophy). So far 246 patients from nine centres (Amsterdam, Bologna, Izmir, Leipzig, M\ufcnster, Moscow, Pisa, Santiago de Compostela, Ulm) have been recruited. With the help from the six centres on the brink of recruitment (Cambridge, Lille, Nicosia, Paris, Porto, Rome) this number is expected to double within the next one or 2 years. Conclusions: A European registry for all patients with lipodystrophy will provide a platform for improved research in the area of lipodystrophy. All physicians from Europe and neighbouring countries caring for patients with lipodystrophy are invited to participate in the ECLip Registry. Study registration: ClinicalTrials.gov (NCT03553420). Registered 14 March 2018, retrospectively registered

Epidemiology of ATTRV30M neuropathy in Cyprus and the modifier effect of complement C1q on the age of disease onset.

BACKGROUND: ATTRV30M amyloidosis is a lethal autosomal dominant sensorimotor and autonomic neuropathy caused by amyloid deposition composed of aggregated misfolded TTR monomers with the V30M mutation. The age of onset in patients with ATTRV30M varies in different foci and the mechanism behind it is still unknown. METHODS: The tertiary neurology center following all ATTRV30M patients in Cyprus was used to collect demographic data to estimate; prevalence, incidence, penetrance, anticipation, time from disease onset to diagnosis and transplantation. Ocular, cardiac and leptomeningeal involvement in transplanted patients was explored. Correlation of C1q tagging SNPs with age of disease onset was carried out. RESULTS: Prevalence and incidence for ATTRV30M neuropathy in Cyprus are 5.4/100,000 and 0.3/100,000 respectively. Mean age of onset is 40.6 years and anticipation is 8.3 years. Penetrance reaches 51% and 75% by the ages of 50 and 80 years respectively. In liver transplanted patients rates of ocular, cardiac and leptomeningeal involvement were estimated to be 60%, 20% and 16%, respectively. C1q polymorphisms correlated with age of disease onset. CONCLUSIONS: ATTRV30M neuropathy has a rising prevalence in Cyprus due to improved survival of patients. Late onset complications are becoming a major problem. Complement C1q appears to be a modifier in this disease

Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants

Background and ObjectivesKCNC2 encodes Kv3.2, a member of the Shaw-related (Kv3) voltage-gated potassium channel subfamily, which is important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain. The objective of this study was to analyze the clinical phenotype, genetic background, and biophysical function of disease-associated Kv3.2 variants.MethodsIndividuals with KCNC2 variants detected by exome sequencing were selected for clinical, further genetic, and functional analysis. Cases were referred through clinical and research collaborations. Selected de novo variants were examined electrophysiologically in Xenopus laevis oocytes.ResultsWe identified novel KCNC2 variants in 18 patients with various forms of epilepsy, including genetic generalized epilepsy (GGE), developmental and epileptic encephalopathy (DEE) including early-onset absence epilepsy, focal epilepsy, and myoclonic-atonic epilepsy. Of the 18 variants, 10 were de novo and 8 were classified as modifying variants. Eight drug-responsive patients became seizure-free using valproic acid as monotherapy or in combination, including severe DEE cases. Functional analysis of 4 variants demonstrated gain of function in 3 severely affected DEE cases and loss of function in 1 case with a milder phenotype (GGE) as the underlying pathomechanisms.DiscussionThese findings implicate KCNC2 as a novel causative gene for epilepsy and emphasize the critical role of KV3.2 in the regulation of brain excitability