Two novel compound heterozygous SAG mutations in an Italian patient with Oguchi disease: A genetic and multimodal retinal imaging study

2021 ◽  
pp. 112067212110274
Author(s):  
Elisabetta Pilotto ◽  
Eva Trevisson ◽  
Elisabetta Beatrice Nacci ◽  
Evelyn Longhin ◽  
Francesca Guidolin ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Retinal Dystrophy ◽  
Retinal Imaging ◽  
Light Condition ◽  
Imaging Study ◽  
Common Finding ◽  
Compound Heterozygous ◽  
Italian Patient ◽  
Pathogenic Variants ◽  
Oguchi Disease

Background: Oguchi disease is a rare autosomal recessive retinal dystrophy, characterized by congenital stationary blindness and caused by pathogenic variants in SAG and GRK1 genes. The present study aimed to report an Italian patient affected by Oguchi disease, evaluated by means of a multimodal retinal imaging study and harboring two novel heterozygous pathogenic variants in the SAG gene. Materials and methods: A 60-year-old female complaining congenital stationary night blindness was investigated through fundus photograph, optical coherence tomography (OCT), electroretinography (ERG), and genetic testing. Results: Fundus examination showed a golden-grayish fundus aspect. The rod response of the scotopic ERG was undetectable and mixed rod-cone response was electronegative. Fundus photographs obtained in light and in prolonged dark-adapted conditions allowed to detect the Mizuo-Nakamura phenomenon. Light condition OCT over the abnormal retinal regions showed high-intensity areas in the outer photoreceptor segment layer, that reduced with prolonged dark adaption. Genetic testing identified two rare heterozygous sequence variants in the SAG gene: NM_000541.5:c.807delA p.(Glu270Lysfs*9) and NM_000541.5:c.1047-1G>C confirming the diagnosis of Oguchi disease. Conclusions: We identified the first Italian compound heterozygous patient harboring two novel alterations in the SAG gene (a frameshift deletion and a splicing variant). The involvement of the SAG gene in Oguchi disease is a common finding in Japanese population, but rarely identified in Caucasians. Clinical suspicion should prompt the molecular analysis of genes associated with this condition.

scholarly journals Extending the phenotypic spectrum of PRPF8, PRPH2, RP1 and RPGR, and the genotypic spectrum of early-onset severe retinal dystrophy

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Michalis Georgiou ◽  
Naser Ali ◽  
Elizabeth Yang ◽  
Parampal S. Grewal ◽  
Tryfon Rotsos ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Early Onset ◽  
Molecular Genetic ◽  
Disease Onset ◽  
Retinal Dystrophy ◽  
Genetic Diagnosis ◽  
Retinal Imaging ◽  
Molecular Genetic Testing ◽  
Phenotypic Spectrum ◽  
Novel Variant

Abstract Purpose To present the detailed retinal phenotype of patients with Leber Congenital Amaurosis/Early-Onset Severe Retinal Dystrophy (LCA/EOSRD) caused by sequence variants in four genes, either not (n = 1) or very rarely (n = 3) previously associated with the disease. Methods Retrospective case series of LCA/EOSRD from four pedigrees. Chart review of clinical notes, multimodal retinal imaging, electrophysiology, and molecular genetic testing at a single tertiary referral center (Moorfields Eye Hospital, London, UK). Results The mean age of presentation was 3 months of age, with disease onset in the first year of life in all cases. Molecular genetic testing revealed the following disease-causing variants: PRPF8 (heterozygous c.5804G > A), PRPH2 (homozygous c.620_627delinsTA, novel variant), RP1 (homozygous c.4147_4151delGGATT, novel variant) and RPGR (heterozygous c.1894_1897delGACA). PRPF8, PRPH2, and RP1 variants have very rarely been reported, either as unique cases or case reports, with limited clinical data presented. RPGR variants have not previously been associated with LCA/EOSRD. Clinical history and detailed retinal imaging are presented. Conclusions The reported cases extend the phenotypic spectrum of PRPF8-, PRPH2-, RP1-, and RPGR-associated disease, and the genotypic spectrum of LCA/EOSRD. The study highlights the importance of retinal and functional phenotyping, and the importance of specific genetic diagnosis to potential future therapy.

Frequency and characterization of mutations in genes in a large cohort of patients referred to MODY registry

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Emily Breidbart ◽  
Liyong Deng ◽  
Patricia Lanzano ◽  
Xiao Fan ◽  
Jiancheng Guo ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Exome Sequencing ◽  
Large Scale ◽  
Age Of Onset ◽  
Family Members ◽  
Ethnically Diverse ◽  
Monogenic Diabetes ◽  
Diabetes Diagnosis ◽  
Pathogenic Variants ◽  
Atypical Diabetes

Abstract Objectives There have been few large-scale studies utilizing exome sequencing for genetically undiagnosed maturity onset diabetes of the young (MODY), a monogenic form of diabetes that is under-recognized. We describe a cohort of 160 individuals with suspected monogenic diabetes who were genetically assessed for mutations in genes known to cause MODY. Methods We used a tiered testing approach focusing initially on GCK and HNF1A and then expanding to exome sequencing for those individuals without identified mutations in GCK or HNF1A. The average age of onset of hyperglycemia or diabetes diagnosis was 19 years (median 14 years) with an average HbA1C of 7.1%. Results Sixty (37.5%) probands had heterozygous likely pathogenic/pathogenic variants in one of the MODY genes, 90% of which were in GCK or HNF1A. Less frequently, mutations were identified in PDX1, HNF4A, HNF1B, and KCNJ11. For those probands with available family members, 100% of the variants segregated with diabetes in the family. Cascade genetic testing in families identified 75 additional family members with a familial MODY mutation. Conclusions Our study is one of the largest and most ethnically diverse studies using exome sequencing to assess MODY genes. Tiered testing is an effective strategy to genetically diagnose atypical diabetes, and familial cascade genetic testing identified on average one additional family member with monogenic diabetes for each mutation identified in a proband.

scholarly journals Extended gene panel testing in lobular breast cancer

2021 ◽  
Author(s):  
Elke M. van Veen ◽  
D. Gareth Evans ◽  
Elaine F. Harkness ◽  
Helen J. Byers ◽  
Jamie M. Ellingford ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Genetic Testing ◽  
Detection Rate ◽  
Gene Panel ◽  
Lobular Breast Cancer ◽  
Germline Variants ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Gene Panel Testing ◽  
Increased Risk

AbstractPurpose: Lobular breast cancer (LBC) accounts for ~ 15% of breast cancer. Here, we studied the frequency of pathogenic germline variants (PGVs) in an extended panel of genes in women affected with LBC. Methods: 302 women with LBC and 1567 without breast cancer were tested for BRCA1/2 PGVs. A subset of 134 LBC affected women who tested negative for BRCA1/2 PGVs underwent extended screening, including: ATM, CDH1, CHEK2, NBN, PALB2, PTEN, RAD50, RAD51D, and TP53.Results: 35 PGVs were identified in the group with LBC, of which 22 were in BRCA1/2. Ten actionable PGVs were identified in additional genes (ATM(4), CDH1(1), CHEK2(1), PALB2(2) and TP53(2)). Overall, PGVs in three genes conferred a significant increased risk for LBC. Odds ratios (ORs) were: BRCA1: OR = 13.17 (95%CI 2.83–66.38; P = 0.0017), BRCA2: OR = 10.33 (95%CI 4.58–23.95; P < 0.0001); and ATM: OR = 8.01 (95%CI 2.52–29.92; P = 0.0053). We did not detect an increased risk of LBC for PALB2, CDH1 or CHEK2. Conclusion: The overall PGV detection rate was 11.59%, with similar rates of BRCA1/2 (7.28%) PGVs as for other actionable PGVs (7.46%), indicating a benefit for extended panel genetic testing in LBC. We also report a previously unrecognised association of pathogenic variants in ATM with LBC.

scholarly journals Bi-allelic variants in MTMR5/SBF1 cause Charcot-Marie-Tooth type 4B3 featuring mitochondrial dysfunction

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Beatrice Berti ◽  
Giovanna Longo ◽  
Francesco Mari ◽  
Stefano Doccini ◽  
Ilaria Piccolo ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Mitochondrial Dysfunction ◽  
Early Onset ◽  
Integrated Approach ◽  
Compound Heterozygous ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Pathogenic Variants ◽  
First Case ◽  
Spine Mri

Abstract Background Charcot-Marie-Tooth disease (CMT) type 4B3 (CMT4B3) is a rare form of genetic neuropathy associated with variants in the MTMR5/SBF1 gene. MTMR5/SBF1 is a pseudophosphatase predicted to regulate endo-lysosomal trafficking in tandem with other MTMRs. Although almost ubiquitously expressed, pathogenic variants primarily impact on the peripheral nervous system, corroborating the involvement of MTMR5/SBF1 and its molecular partners in Schwann cells-mediated myelinization. Case presentation We report a case of severe CMT4B3 characterized by early-onset motor and axonal polyneuropathy in an Italian child in absence of any evidence of brain and spine MRI abnormalities or intellectual disability and with a biochemical profile suggestive of mitochondrial disease. Using an integrated approach combining both NGS gene panels and WES analysis, we identified two novel compound heterozygous missense variants in MTMR5/SBF1 gene, p.R763H (c.2291G > A) and p.G1064E (c.3194G > A). Studies in muscle identified partial defects of oxidative metabolism. Conclusion We describe the first case of an early onset severe polyneuropathy with motor and axonal involvement, due to recessive variants in the MTMR5/SBF1 gene, with no evidence of brain and spine MRI abnormalities, intellectual disability, no clinical and neurophysiological evidences of distal sensory impairment, and rapid neuromuscular deterioration. This report suggests that MTMR5/SBF1 should be considered in cases of infantile-onset CMT with secondary mitochondrial dysfunction.

Combined Muscle Biopsy and Comprehensive Electrophysiology in General Anesthesia is Valuable in Diagnosis of Neuromuscular Disease in Children

2021 ◽  
Author(s):  
Christina E. Hoei-Hansen ◽  
Marie L. B. Tygesen ◽  
Morten Dunø ◽  
John Vissing ◽  
Martin Ballegaard ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Muscle Biopsy ◽  
Neuromuscular Disease ◽  
Genetic Diagnosis ◽  
Congenital Myasthenic Syndrome ◽  
Diagnostic Quality ◽  
Pathogenic Variants ◽  
Combined Use ◽  
Myasthenic Syndrome ◽  
Size Variability

Abstract Aim The diagnostic workup in patients with delayed motor milestones suspected of having either myopathy or a congenital myasthenic syndrome is complex. Our hypothesis was that performance of a muscle biopsy and neurophysiology including stimulated single-fiber electromyography during an anesthetic procedure, combined with genetic testing has a high diagnostic quality. Materials and Methods Clinical and paraclinical data were retrospectively collected from 24 patients aged from 1 month to 10 years (median: 5.2 years). Results Neurophysiology examination was performed in all patients and was abnormal in 11 of 24. No patients had findings suggestive of a myasthenic syndrome. Muscle biopsy was performed in 21 of 24 and was normal in 16. Diagnostic findings included nemaline rods, inclusion bodies, fiber size variability, and type-II fiber atrophy. Genetic testing with either a gene panel or exome sequencing was performed in 18 of 24 patients, with pathogenic variants detected in ACTA1, NEB, SELENON, GRIN2B, SCN8A, and COMP genes. Conclusion Results supporting a neuromuscular abnormality were found in 15 of 24. In six patients (25%), we confirmed a genetic diagnosis and 12 had a clinical neuromuscular diagnosis. The study suggests that combined use of neurophysiology and muscle biopsy in cases where genetic testing does not provide a diagnosis can be useful in children with delayed motor milestones and clinical evidence of a neuromuscular disease.

scholarly journals Assessment of genetic referrals and outcomes for women with triple negative breast cancer in regional cancer centres in Australia

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Lucie G. Hallenstein ◽  
Carol Sorensen ◽  
Lorraine Hodgson ◽  
Shelly Wen ◽  
Justin Westhuyzen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Genetic Testing ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cancer Genetics ◽  
Eligibility Criteria ◽  
Pathogenic Variants ◽  
Genetics Services ◽  
Age Of Diagnosis ◽  
Over Time

Abstract Background Guidelines for referral to cancer genetics service for women diagnosed with triple negative breast cancer have changed over time. This study was conducted to assess the changing referral patterns and outcomes for women diagnosed with triple negative breast cancer across three regional cancer centres during the years 2014–2018. Methods Following ethical approval, a retrospective electronic medical record review was performed to identify those women diagnosed with triple negative breast cancer, and whether they were referred to a genetics service and if so, the outcome of that genetics assessment and/or genetic testing. Results There were 2441 women with newly diagnosed breast cancer seen at our cancer services during the years 2014–2018, of whom 237 women were diagnosed with triple negative breast cancer. Based on age of diagnosis criteria alone, 13% (31/237) of our cohort fulfilled criteria for genetic testing, with 81% (25/31) being referred to a cancer genetics service. Of this group 68% (21/31) were referred to genetics services within our regions and went on to have genetic testing with 10 pathogenic variants identified; 5x BRCA1, 4x BRCA2 and × 1 ATM:c.7271 T > G. Conclusions Referral pathways for women diagnosed with TNBC to cancer genetics services are performing well across our cancer centres. We identified a group of women who did not meet eligibility criteria for referral at their time of diagnosis, but would now be eligible, as guidelines have changed. The use of cross-discipline retrospective data reviews is a useful tool to identify patients who could benefit from being re-contacted over time for an updated cancer genetics assessment.

MO1027EFFICACY OF CALCINEURIN INHIBITORS IN CHILDREN WITH MONOGENIC STEROID-RESISTANT NEPHROTIC SYNDROME

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Larisa Prikhodina ◽  
Svetlana Papizh ◽  
Inna Povolotskaya
Keyword(s):  
Nephrotic Syndrome ◽  
Calcineurin Inhibitors ◽  
Compound Heterozygous ◽  
Target Level ◽  
Steroid Resistant ◽  
Steroid Resistant Nephrotic Syndrome ◽  
Pathogenic Variants ◽  
Nail Patella Syndrome

Abstract Background and Aims Monogenic causes of steroid-resistant nephrotic syndrome (SRNS) have been reported for up to one-third of children depending on age of the disease onset. Immunosuppressive treatment of genetic SRNS with calcineurin inhibitors (CNIs) is still controversial. The aim of the study was to investigate the efficacy of CNIs with focus on inducing remission and long-term kidney function in children with monogenic SRNS. Method Retrospective analysis of efficacy CNIs in five children (2M/3F) with monogenic SRNS was performed. Kidney biopsy prior CNIs revealed FSGS (n=4) and MCD (n=1). The initial cyclosporine (CsA) dose was 5 mg/kg/24h to keep a target level of 80-150 ng/ml and tacrolimus (TAC) - 0.1 mg/kg/24h to achieve a target level of 5-10 ng/ml. CsA took all 5 patients with subsequent switching to TAC in 2 children due to cosmetic side effects. The median follow-up period was 165.0 (IQR: 59.0; 185.5) months. Next generation sequencing (NGS) was used for identification of pathogenic variants in all patients. Results The median age at onset of monogenic SRNS was 33.0 (IQR: 16.5; 63.0) months. 2/5 (40%) patients presented with acute SRNS, 1/5 (20%) child with infantile NS, 1/5 (20%) - with isolated nephrotic range proteinuria with hypoalbuminemia and 1/5 (20%) - with NS and extrarenal features of Nail-Patella syndrome. NGS identified previously described pathogenic variants in all 5 children, including NPHS2 homozygous c.28dup (p.Glu87Ter) (n=1), NPHS2 compound heterozygous c.868G&gt;A (p.Val290Met) in combination with c.686G&gt;A (p.Arg229Gln) (n=1), LMX1B heterozygous c.788T&gt;G (p.Val263Gly) (n=1), LMX1B heterozygous c.737G&gt;A (p.Arg246Gln) (n=1), and COL4A3 heterozygous c.2962G&gt;A (p.Gly988Arg) variant (n=1). The median time from diagnosis to initiation of CNIs treatment was 72.0 (IQR: 33.0; 93.0) months. CNIs induced complete remission in 2/5 (40%) patients, presented with acute SRNS, including one girl with MCD due to NPHS2 compound heterozygous variants with mutation-dependent pathogenicity of one (p.R229Q) of them and one boy with FSGS due to COL4A3 heterozygous variant (n=1). Partial remission was induced by CNIs in 2/5 (40%) girls with FSGS due to LMX1B heterozygous variants with isolated SRNS (n=1) and Nail-Patella syndrome (n=1). The median duration of CNIs treatment to obtain complete or partial remission was 13.5 (IQR: 6.8; 15.8) months. Acute CNIs-associated nephrotoxicity had 2 patients with LMX1B variants. At the last follow up full and partial responders to CNIs treatment aged of 16.5 (IQR: 11.8; 17.5) years had CKD-1 (n=3) and CKD-2 (n=1). 1/5 (20%) boy with NPHS2-associated infantile NS was CNI resistant and developed CKD-5 at the age of 6.5 years with subsequent living related kidney transplantation. Conclusion We found that 4/5 (80%) children with monogenic SRNS demonstrated partial or full response to CNIs treatment with stable long-term kidney function. We assume that CNIs might improve podocyte function by stabilization of their cytoskeleton disrupted in patients with monogenic SRNS.

Development and assessment of an accessible communication system for population-based genetic testing: Method/design (Preprint)

2021 ◽  
Author(s):  
Tara Coffin ◽  
Deborah Bowen ◽  
Elizabeth Swisher ◽  
Karen Lu ◽  
Karen Lu ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Communication System ◽  
Formative Evaluation ◽  
Online Communication ◽  
Implementation Process ◽  
Usability Testing ◽  
Population Based ◽  
Ovarian Cancer Risk ◽  
Online System ◽  
Pathogenic Variants

BACKGROUND Genetic testing uptake is low, despite the well-established connection between pathogenic variants in certain cancer-linked susceptibility genes and ovarian cancer risk. Given that most major insurers cover genetic testing for those with a family history suggestive of hereditary cancer, the issue may lie in access to genetic testing. OBJECTIVE To present the development and formative evaluation of the multi-step online communication system required to support the democratization of genetic testing. METHODS While designing the multi-step online communication system, we considered various barriers and facilitators to genetic testing, guided by Levesque et al.’s dimensions of accessibility. In addition to conducting usability testing, we performed ongoing assessments focusing on function of the online system and participant response rates, with the goal of continuing to make modifications to the online communication system as it is in use. RESULTS The combined approach of usability testing and expert user experience (UX) consultation resulted in several modifications to the multi-step online communication system, including changes that related to imagery and content, web-accessibility, and general organization of the online system. All recommendations were made with the goal of improving the overall accessibility of the online communication system. CONCLUSIONS A multi-step online communication system appears to be an effective way to address many potential barriers to access, which may otherwise make genetic testing difficult for at-risk individuals to participate in. Importantly, some dimensions of access were easy to assess prior to study recruitment opening, but other aspects of the communication system required ongoing assessment during the implementation process of the Making Genetic Testing Accessible (MAGENTA) study.

scholarly journals A post mortem assessment of a 25-year-old man with ascending aortic dissection and a novel MYLK variant

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Katelyn Hodge ◽  
Katherine G. Spoonamore ◽  
Christopher B. Griffith ◽  
David D. Weaver ◽  
Patricia B.S. Celestino-Soper ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Aortic Aneurysm ◽  
Aortic Dissection ◽  
Thoracic Aortic Aneurysm ◽  
Aortic Rupture ◽  
Clinical Consequence ◽  
Post Mortem ◽  
Variant Of Uncertain Significance ◽  
Pathogenic Variants ◽  
Aortic Aneurysm And Dissection

We report on the process of <em>post mortem</em> evaluation and genetic testing following the death of a 25-year-old man due to ascending aortic dissection leading to aortic rupture. Following the negative clinical testing of a 12- gene thoracic aortic aneurysm and dissection panel, research testing revealed a novel c.5732A&gt;T (p.E1911V) variant in exon 34 of the MYLK gene (NM_053025). Two likely pathogenic variants in this gene have been reported previously in individuals with familial thoracic aortic aneurysm and dissection. Given the unclear clinical consequence of the variant found in our proband, we have classified this change as a variant of uncertain significance. In addition to discussing the complexity involved in variant interpretation, we recognize the need for additional research for more accurate <em>MYLK</em> interpretation. Finally, we comment on the unique challenges of <em>post mortem</em> genetic testing.

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