Search

Background: Advances in genomics provide improved opportunities for diagnosis of complex neurogenetic disorders, yet the optimal approach to translate these benefits to the outpatient clinic is unclear. Aims: We retrospectively reviewed referral indications and outcomes of an integrated multidisciplinary team (MDT) clinic pathway for adults with suspected neurogenetic disorders. The associated cost implications were estimated. Methods: Consecutive patients who attended the neurogenomics clinic from January 2017 to April 2020 were included. The clinic comprised neurologists, clinical geneticists and genetic counsellors, who assessed each patient concurrently. Results: Ninety‐nine new patients were referred spanning 45 different clinical diagnoses. Following MDT clinical assessment, 23% (23/99) of referral diagnoses were revised prior to molecular testing. Eighty‐one patients (82%) underwent genetic testing, including 43 exome‐based panels, 15 whole‐genome sequencing, 14 single gene tests, 27 repeat‐primed polymerase chain reaction testing and two chromosomal microarrays. Overall, 33/99 patients (33%) received a diagnosis, either a molecular diagnosis (n = 24, of which 22 were diagnostic and two were predictive) or a clinical diagnosis (n = 9). Of the clinical diagnosis cohort, five patients received a diagnosis without molecular testing and four patients whose negative testing (one diagnostic and three predictive) allowed exclusion of genetic differentials and, hence, confirmation of clinical diagnoses. The diagnostic rate following MDT and diagnostic testing was 30% (28/94), excluding the five predictive testing cases. MDT assessment aligned with eventual molecular diagnoses in 96% of cases. The estimated average costs were AU$1386 per patient undergoing MDT assessment and AU$4159 per diagnosis achieved. Conclusions: We present an integrated multidisciplinary neurogenomics clinic pathway providing a diagnostic yield of 33% (30% excluding predictive testing cases), with costing implications. The relatively high diagnostic yield may be attributed to multidisciplinary input integrating accurate phenotyping of complex disorders and interpretation of genomic findings. [ABSTRACT FROM AUTHOR]

We report the case of a young woman who presented at age 10 years with height on the tenth centile, brachydactyly type E and mild developmental delay. Biochemistry and hormonal profiles were normal. Differential diagnoses considered included Albright hereditary osteodystrophy without hormone resistance (a.k.a pseudopseudohypoparathyroidism), 2q37 microdeletion syndrome and acrodysostosis. She had a normal karyotype and normal FISH of 2q37. Whole genome sequencing (WGS) identified a mutation in the ANKRD11 gene associated with KBG syndrome. We review the clinical features of the genetic syndromes considered, and suggest KBG syndrome be considered in patients presenting with syndromic brachydactyly type E, especially if short stature and developmental delay are also present. [ABSTRACT FROM AUTHOR]

Background: Heterozygous KMT2B variants are a common cause of dystonia. A novel synonymous KMT2B variant, c.5073C>T (p.Gly1691=) was identified in an individual with childhood‐onset progressive dystonia. Methods: The splicing impact of c.5073C>T was assessed using an in vitro exon‐trapping assay. The genomic region of KMT2B exons 23–26 was cloned into the pSpliceExpress plasmid between exon 2 and 3 of the rat Ins2 gene. The c.5073C>T variant was then introduced through site‐directed mutagenesis. The KMT2B wild‐type and c.5073C>T plasmids were transfected separately into HeLa cells and RNA was extracted 48 hours after transfection. The RNA was reverse transcribed to produce cDNA, which was PCR amplified using primers annealing to the flanking rat Ins2 sequences. Results: Sanger sequencing of the PCR products revealed that c.5073C>T caused a novel splice donor site and therefore a 5‐bp deletion of KMT2B exon 23 in mature mRNA, leading to a coding frameshift and premature stop codon (p.Lys1692AsnfsTer7). Conclusion: To our knowledge, this is the first report of a KMT2B synonymous variant associated with dystonia. Reassessment of synonymous variants may increase diagnostic yield for inherited disorders including monogenic dystonia. This is of clinical importance, given the generally favourable response to deep brain stimulation for KMT2B‐related dystonia. [ABSTRACT FROM AUTHOR]

This sub-study of the Australian Genomics Cardiovascular Genetic Disorders Flagship sought to conduct the first nation-wide audit in Australia to establish the current practices across cardiac genetics clinics. An audit of records of patients with a suspected genetic heart disease (cardiomyopathy, primary arrhythmia, autosomal dominant congenital heart disease) who had a cardiac genetics consultation between 1st January 2016 and 31 July 2018 and were offered a diagnostic genetic test. This audit included 536 records at multidisciplinary cardiac genetics clinics from 11 public tertiary hospitals across five Australian states. Most genetic consultations occurred in a clinic setting (90%), followed by inpatient (6%) and Telehealth (4%). Queensland had the highest proportion of Telehealth consultations (9% of state total). Sixty-six percent of patients had a clinical diagnosis of a cardiomyopathy, 28% a primary arrhythmia, and 0.7% congenital heart disease. The reason for diagnosis was most commonly as a result of investigations of symptoms (73%). Most patients were referred by a cardiologist (85%), followed by a general practitioner (9%) and most genetic tests were funded by the state Genetic Health Service (73%). Nationally, 29% of genetic tests identified a pathogenic or likely pathogenic gene variant; 32% of cardiomyopathies, 26% of primary arrhythmia syndromes, and 25% of congenital heart disease. We provide important information describing the current models of care for genetic heart diseases throughout Australia. These baseline data will inform the implementation and impact of whole genome sequencing in the Australian healthcare landscape. • We describe the current models of care for genetic heart diseases throughout Australia • Genetic testing identified a causative variant in 29% of cases • Data will inform the implementation and impact of whole genome sequencing in Australian healthcare [ABSTRACT FROM AUTHOR]

The capability of genetic technologies is expanding rapidly in the field of inherited eye disease. New genetic testing approaches will deliver a step change in the ability to diagnose and extend the possibility of targeted treatments. However, evidence is lacking about the benefits of genetic testing to support service planning. Here, we report qualitative data about retinal dystrophy families' experiences of genetic testing in United Kingdom. The data were part of a wider study examining genetic eye service provision. Twenty interviewees from families in which a causative mutation had been identified by a genetic eye clinic were recruited to the study. Fourteen interviewees had chosen to have a genetic test and five had not; one was uncertain. In-depth telephone interviews were conducted allowing a thorough exploration of interviewees' views and experiences of the benefits of genetic counselling and testing. Transcripts were analysed using thematic analysis. Both affected and unaffected interviewees expressed mainly positive views about genetic testing, highlighting benefits such as diagnostic confirmation, risk information, and better preparation for the future. Negative consequences included the burden of knowledge, moral dilemmas around reproduction, and potential impact on insurance. The offer of genetic testing was often taken up, but was felt unnecessary in some cases. Interviewees in the study reported many benefits, suggesting genetic testing should be available to this patient group. The benefits and risks identified will inform future evaluation of models of service delivery. This research was part of a wider study exploring experiences of families with retinal dystrophy. [ABSTRACT FROM AUTHOR]

Background UK genetic ophthalmology services for patients with retinal dystrophy (RD) are variable. Little research exists to define service requirements, or expectations, of patients and their families. This study aimed to explore the views and perceived benefits of genetic ophthalmology services among members of families with RD. Methods Twenty participants with known RD mutations were recruited through UK genetic ophthalmic clinics. Semistructured qualitative interviews explored interviewees' perceptions of the role of these services. Interviews were transcribed verbatim and analysed using inductive thematic analysis. Results Interviewees' expectations and requirements of genetic ophthalmology services were wide-ranging and often perceived to be unmet. Participant expectations were classified in three groups: (1) Medical expectations included obtaining a diagnosis and information about disease/prognosis, genetic risks and research (2) Psychosocial expectations related to participants' need for support in adjusting to RD (3) Practical expectations included the desire for information about welfare and support. Conclusions Expectations of RD families for clinical services are complex, encompassing a range of healthcare specialties. Services that align to these expectations will need to reach beyond the diagnostic arena and provide practical and psychosocial support. The identification of measurable outcomes will facilitate future development and evaluation of service delivery models. Many of the expectations identified here map to an existing, previously validated, outcomes framework for clinical genetic services. However, an additional outcome domain, labelled 'Independence' was also identified; this could either be specific to vision loss or relate generally to disability caused by genetic conditions. [ABSTRACT FROM AUTHOR]

. Purpose: To describe the clinical phenotype and the molecular pathology in a group of patients with congenital stationary night blindness due to mutations in GRM6, a gene encoding the ON bipolar metabotropic glutamate receptor 6 (mGluR6). Methods: Nine patients from seven families (age range, 7-75; median, 10 years) with a clinical diagnosis of autosomal recessive complete congenital stationary night blindness were ascertained. Clinical examination, imaging and electrophysiological assessment were performed. The coding region and intron-exon boundaries of GRM6 were sequenced. Results: The median visual acuity for the cohort was 0.2 logMAR (range 0-3). Most patients had myopic astigmatism with the median spherical equivalent being −5.375 dioptres (−0.125 to −18.75). Fundoscopy was within normal limits in 15 eyes; there was severe myopic maculopathy in three eyes. Other secondary complications included face turn because of nystagmus and strabismic amblyopia. All patients had electronegative dark-adapted bright white flash electroretinograms (ERGs) consistent with dysfunction occurring postphototransduction. In the two oldest subjects (aged 75 and 58 years), there was additional photoreceptor dysfunction in keeping with myopic degeneration. ON-OFF ERGs showed generalized cone ON bipolar system dysfunction in all five patients tested. Pattern ERG P50 was normal ( Ν = 1), subnormal ( N = 2) or undetectable ( N = 2). Nine mutations in GRM6 were detected in all seven families; six of these changes were novel. Conclusions: The phenotype associated with GRM6 mutation is variable in terms of presentation, refractive error, visual acuity and macular function. ERGs are electronegative and suggest ON-pathway dysfunction. [ABSTRACT FROM AUTHOR]

Aim To describe the clinical features of a case series of patients with unilateral vitelliform maculopathy and the results of screening BEST1 and PRPH2 for diseasecausing mutations. Design/Methods This was a retrospective case series study of six patients ascertained over a 2-year period. Ophthalmological examination, fundus photography, autofluorescence imaging, optical coherence tomography and detailed electrophysiological assessment were undertaken. Blood samples were taken for DNA extraction and mutation screening of BEST1 and PRPH2 was performed. Results Six patients (3 men and 3 women) with unilateral vitelliform maculopathy were identified, ranging in age from 30 to 68 years. Vision in the affected eye ranged from 20/10 to 20/100. There was no clinical, retinal imaging or electrophysiological evidence of fellow eye involvement. Direct sequencing of BEST1 and PRPH2 did not reveal any disease-causing variants. Conclusions A case series of patients is reported with an unusual unilateral vitelliform phenotype, often associated with good visual function. The patients do not have the typical characteristics associated with agerelated maculopathy or any inherited macular disorders, such as Best vitelliform macular dystrophy. Molecular screening of the candidate genes BEST1 and PRPH2 revealed no mutations. [ABSTRACT FROM AUTHOR]

Purpose: To describe phenotypic variability and to report novel mutational data in patients with gyrate atrophy. Design: Retrospective case series. Participants: Seven unrelated patients (10 to 52 years of age) with clinical and biochemical evidence of gyrate atrophy. Methods: Detailed ophthalmologic examination, fundus photography, fundus autofluorescence (FAF) imaging, spectral-domain optical coherence tomography, and microperimetry testing were performed. The coding region and intron–exon boundaries of ornithine aminotransferase (OAT) were analyzed. OAT mRNA was isolated from peripheral blood leucocytes of 1 patient and analyzed. Main Outcome Measures: OAT mutation status and resultant clinical, structural, and functional characteristics. Results: Funduscopy revealed circular areas of chorioretinal atrophy, and FAF imaging showed sharply demarcated areas of increased or preserved signal in all 7 patients. Spectral-domain optical coherence tomography revealed multiple intraretinal cystic spaces and hyperreflective deposit in the ganglion cell layer of all study subjects. Round tubular, rosette-like structures located in the outer nuclear layer of the retinae of the 4 older patients were observed (termed outer retinal tubulation). Thickening was evident in the foveolae of younger patients, despite the posterior pole appearing relatively preserved. Macular function, assessed by microperimetry, was preserved over areas of normal or increased autofluorescence. However, sensitivity was reduced even in structurally intact parts of the retina. The molecular pathologic features were determined in all study subjects: 9 mutations, 4 novel, were detected in the OAT gene. OAT mRNA was isolated from blood leukocytes, and monoallelic expression of a mutated allele was demonstrated in 1 patient. Conclusions: Fundus autofluorescence imaging can reveal the extent of neurosensory dysfunction in gyrate atrophy patients. Macular edema is a uniform finding; the fovea is relatively thick in early stages of disease and retinal tubulation is present in advanced disease. Analysis of leukocyte RNA complements the high sensitivity of conventional sequencing of genomic DNA for mutation detection in this gene. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. [Copyright &y& Elsevier]

We have identified KIF11 mutations in individuals with syndromic autosomal-dominant microcephaly associated with lymphedema and/or chorioretinopathy. Initial whole-exome sequencing revealed heterozygous KIF11 mutations in three individuals with a combination of microcephaly and lymphedema from a microcephaly-lymphedema-chorioretinal-dysplasia cohort. Subsequent Sanger sequencing of KIF11 in a further 15 unrelated microcephalic probands with lymphedema and/or chorioretinopathy identified additional heterozygous mutations in 12 of them. KIF11 encodes EG5, a homotetramer kinesin motor. The variety of mutations we have found (two nonsense, two splice site, four missense, and six indels causing frameshifts) are all predicted to have an impact on protein function. EG5 has previously been shown to play a role in spindle assembly and function, and these findings highlight the critical role of proteins necessary for spindle formation in CNS development. Moreover, identification of KIF11 mutations in patients with chorioretinopathy and lymphedema suggests that EG5 is involved in the development and maintenance of retinal and lymphatic structures. [ABSTRACT FROM AUTHOR]

X-linked cone and cone-rod dystrophies (XLCOD and XLCORD) are a heterogeneous group of progressive disorders that solely or primarily affect cone photoreceptors. Mutations in exon ORF15 of the RPGR gene are the most common underlying cause. In a previous study, we excluded RPGR exon ORF15 in some families with XLCOD. Here, we report genetic mapping of XLCOD to Xq26.1-qter. A significant LOD score was detected with marker DXS8045 (Zmax = 2.41 [θ = 0.0]). The disease locus encompasses the cone opsin gene array on Xq28. Analysis of the array revealed a missense mutation (c. 529T>C [p. W177R]) in exon 3 of both the long-wavelength-sensitive (LW, red) and medium-wavelength-sensitive (MW, green) cone opsin genes that segregated with disease. Both exon 3 sequences were identical and were derived from the MW gene as a result of gene conversion. The amino acid W177 is highly conserved in visual and nonvisual opsins across species. We show that W177R in MW opsin and the equivalent W161R mutation in rod opsin result in protein misfolding and retention in the endoplasmic reticulum. We also demonstrate that W177R misfolding, unlike the P23H mutation in rod opsin that causes retinitis pigmentosa, is not rescued by treatment with the pharmacological chaperone 9-cis-retinal. Mutations in the LW/MW cone opsin gene array can, therefore, lead to a spectrum of disease, ranging from color blindness to progressive cone dystrophy (XLCOD5). [ABSTRACT FROM AUTHOR]

Complete congenital stationary night blindness (cCSNB) is associated with loss of function of rod and cone ON bipolar cells in the mammalian retina. In humans, mutations in NYX and GRM6 have been shown to cause the condition. Through the analysis of a consanguineous family and screening of nine additional pedigrees, we have identified three families with recessive mutations in the gene TRPM1 encoding transient receptor potential cation channel, subfamily M, member 1, also known as melastatin. A number of other variants of unknown significance were found. All patients had myopia, reduced central vision, nystagmus, and electroretinographic evidence of ON bipolar cell dysfunction. None had abnormalities of skin pigmentation, although other skin conditions were reported. RNA derived from human retina and skin was analyzed and alternate 5′ exons were determined. The most 5' exon is likely to harbor an initiation codon, and the protein sequence is highly conserved across vertebrate species. These findings suggest an important role of this specific cation channel for the normal function of ON bipolar cells in the human retina. [ABSTRACT FROM AUTHOR]