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Purpose: To describe a case of retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) to enhance early recognition of this often-missed diagnosis. Methods: A case report is presented. Results: A 50-year-old woman with a history of Raynaud phenomenon, memory difficulties, and a family history of strokes was referred for evaluation of a bilateral, small-vessel, occlusive disease refractory to immunosuppressive therapy. An extensive workup for treatable causes was unrevealing. Fifteen months after presentation, brain imaging showed white-matter lesions and dystrophic calcification, which led to the discovery of a pathogenic variant in TREX1 and the diagnosis of RVCL-S. Conclusions: Retina specialists play a critical role in the timely diagnosis of RVCL-S. Although the findings in this condition can mimic those in other common retinal vascular disorders, there are key characteristics that increase the suspicion for RVCL-S. Early recognition might decrease unnecessary therapies and procedures.

Neurofibromatosis type 1 (NF1) is a common neurocutaneous disorder characterized by development of pigmentary skin changes, neurogenic tumors, and other manifestations involving multiple organ systems. Penetrance is complete, though expressivity is quite variable even among the family members. Given that NF1 is a common hereditary condition, existence of a second genetic disorder in NF1 patients is not unexpected. During comprehensive evaluations of individuals with NF1, we encountered 11 patients with dual diagnosis who contributed to phenotypic complexity and challenges for long-term management. Examples include Prader-Willi Syndrome, Autosomal Dominant Polycystic Kidney Disease, Down syndrome, infantile myofibromatosis, Craniosynostosis, cleft lip and palate, 47,XYY, 22q11.2 duplication, 15q13.3 deletion syndrome, and BRCA2- and ATM- related cancer predisposition syndromes. Presence of dysmorphism, developmental delay, atypical tumors, and family history of other genetic disorders including cancers appears as determinants to consider a second genetic etiology and helps to differentiate from an extreme phenotypic spectrum of NF1. Clinicians should have high index of suspicion to exclude coexisting disorders, as apart from providing comprehensive medical care. This also has potential implications in genetic counseling. Long-term effects of the synergistic mechanisms leading to phenotypic complexity and patient outcomes are yet to be characterized, with follow-up needed.

A 57-year-old woman presented with a 20-year history of progressive lower extremity weakness, spasticity, and proprioception deficits. She was given a diagnosis of primary progressive multiple sclerosis at age 38. Her Achilles tendons were enlarged (figure 1). Brain MRI was normal. Spine MRI demonstrated T2-hyperintense signal involving the posterior and lateral columns (figure 2). Serum cholestanol level was elevated. CYP27A1 gene sequencing revealed 2 pathogenic variants, c.1183C>T(p.Arg395Cys) and c.410G>A(p.Arg137Gln), confirming the diagnosis of cerebrotendinous xanthomatosis (CTX). Spinal xanthomatosis is a rare variant of CTX presenting with progressive corticospinal and posterior column signs.1 Early treatment with chenodeoxycholic acid may improve outcomes.2

Purpose Exome sequencing often identifies pathogenic genetic variants in patients with undiagnosed diseases. Nevertheless, frequent findings of variants of uncertain significance necessitate additional efforts to establish causality before reaching a conclusive diagnosis. To provide comprehensive genomic testing to patients with undiagnosed disease, we established an Individualized Medicine Clinic, which offered clinical exome testing and included a Translational Omics Program (TOP) that provided variant curation, research activities, or research exome sequencing. Methods From 2012 to 2018, 1101 unselected patients with undiagnosed diseases received exome testing. Outcomes were reviewed to assess impact of the TOP and patient characteristics on diagnostic rates through descriptive and multivariate analyses. Results The overall diagnostic yield was 24.9% (274 of 1101 patients), with 174 (15.8% of 1101) diagnosed on the basis of clinical exome sequencing alone. Four hundred twenty-three patients with nondiagnostic or without access to clinical exome sequencing were evaluated by the TOP, with 100 (9% of 1101) patients receiving a diagnosis, accounting for 36.5% of the diagnostic yield. The identification of a genetic diagnosis was influenced by the age at time of testing and the disease phenotype of the patient. Conclusion Integration of translational research activities into clinical practice of a tertiary medical center can significantly increase the diagnostic yield of patients with undiagnosed disease.

INTRODUCTION Spontaneous coronary artery dissection (SCAD) is a term used to define a spontaneous separation of the coronary artery wall not related to underlying risk factors, such as trauma or underlying atherosclerotic disease. While SCAD has a range of different etiologies, with fibromuscular dysplasia being the most common, most cases of SCAD have no concomitant arteriopathy. CASE REPORT Here we describe a case of a patient who presented to our institution with SCAD and evidence of an asymptomatic arteriopathy involving extracranial segments of the carotid and vertebral arteries, later found to have a pathogenic variant in the FBN1 gene and ultimately diagnosed with Marfan syndrome. This has only been rarely described in the literature as an etiology for SCAD. CONCLUSION Although rare, it is important to consider underlying connective tissue disorders in patients presenting with spontaneous coronary artery dissection and arteriopathy without underlying cardiovascular risk factors.

Introduction - The COVID 19 pandemic led to restrictions on the conventional ways of healthcare delivery. Telemedicine provided a viable solution that was in line with the social distancing policies imposed to minimize disease transmission. This demanded physicians adapt to new ways of healthcare delivery. We surveyed geneticists across the country to determine their experience and to ascertain if telegenetics will be a lasting change. Materials and Methods - A 23 item standardized survey was distributed to various US-based geneticists via email and other social media platforms focusing on their experience of providing care via telemedicine. Results - We received 69 responses from physicians across 26 states. Of these, 91% practiced in academia. 70% responded that pediatric genetics takes up more than 50% of their practice. 68% had over 50% of their practice switch to telemedicine. 77% felt they could provide adequate care via telemedicine and 94% of providers would like to continue telemedicine post-pandemic. Conclusion - The future of telemedicine looks promising as the majority of clinicians would like to routinely use telemedicine post-pandemic. Uniform guidelines for use of telemedicine in genetics may need to be proposed by professional societies and supported by federal laws.

Primary mitochondrial diseases are a heterogeneous group of disorders that result from defects of the oxidative phosphorylation system of the mitochondria. Often underrecognized, mitochondrial diseases are uncommon (estimated incidence, 1 in 10,000 live births). Mitochondria are double-membrane–bound cytoplasmic organelles whose primary function is to provide energy (ie, adenosine triphosphate [ATP]) from the breakdown of carbohydrates, protein, and lipids by means of the electron transport chain and the oxidative phosphorylation system. The respiratory chain of mitochondria, located in the inner mitochondrial membrane, consists of 5 multimeric protein complexes (complexes I-IV and ATP synthase [complex V]). The structural proteins of these complexes are encoded by both mitochondrial and nuclear genes. Therefore, primary mitochondrial disorders can follow a maternal or mendelian inheritance pattern.

BACKGROUND The COVID 19 pandemic led to restrictions on the conventional ways of healthcare delivery. Telemedicine provided a viable solution that was in line with the social distancing policies imposed to minimize disease transmission. This demanded physicians adapt to new ways of healthcare delivery. OBJECTIVE We surveyed geneticists across the country to determine their experience and to ascertain if telegenetics will be a lasting change. METHODS A 23 item standardized survey was distributed to various US-based geneticists via email and other social media platforms focusing on their experience of providing care via telemedicine. RESULTS We received 69 responses from physicians across 26 states. Of these, 91% practiced in academia. 70% responded that pediatric genetics takes up more than 50% of their practice. 68% had over 50% of their practice switch to telemedicine. 77% felt they could provide adequate care via telemedicine and 94% of providers would like to continue telemedicine post-pandemic. CONCLUSIONS The future of telemedicine looks promising as the majority of clinicians would like to routinely use telemedicine post-pandemic. Uniform guidelines for use of telemedicine in genetics may need to be proposed by professional societies and supported by federal laws.

Noonan syndrome (NS) is an autosomal dominant condition with variable expressivity most commonly due to a germline pathogenic variant in PTPN11, which encodes the protein tyrosine phosphatase SHP-2. Gain-of-function variants in PTPN11 are known to promote oncogenic behavior in affected tissues. We report the clinical description of a young adult male presenting with relapsing ganglioneuromas, dysmorphic features, cardiac abnormalities, and multiple lentigines, strongly suspicious for NS. Solid tumor testing identified the recurrent pathogenic c.922G>A (p.Asn308Asp) in PTPN11. Proband and parental blood sampling testing confirmed c.922G>A as a de novo germline alteration. Comprehensive literature review of solid tumors specifically associated to PTPN11, indicates that this is the first documentation of ganglioneuroma and its clinical recurrence after resection in conjunction with a genetically confirmed NS diagnosis. The findings in our patient further extend the list of neuroblastic and neural crest-derived neoplasms associated with this condition.

Background Dual diagnoses in genetics practice are not uncommon and patients with dual diagnosis often present with complex and challenging phenotypes. A combination of meticulous phenotyping and molecular genetic techniques are essential in solving these diagnostic odysseys. Methods Clinical features and genetic workup of a patient presenting with incidental schwannomatosis. Results A 19‐year‐old male presented with incidental painless schwannomatosis in the background of macrocephaly, distinctive facies, and learning disability. Comprehensive genetic testing with gene panel and chromosomal microarray led to a dual diagnosis of LZTR1‐related schwannomatosis and 7q11.23 duplication syndrome. Conclusion We emphasize the need for high index of suspicion and comprehensive genetic testing in complex phenotypes. Interrogation of the interplay between the pathogenic variants in multiple genes could improve our understanding of the pathophysiologic pathways and contribute to therapeutic discoveries., A nineteen year old male presented with incidental painless schwannomatosis in the background of macrocephaly, distinctive facies and learning disability. Comprehensive genetic testing with gene panel and chromosomal microarray led to a dual diagnosis of LZTR1 related schwannomatosis and 7q11.23 duplication syndrome. We emphasize the need for high index of suspicion and comprehensive genetic testing in complex phenotypes. Interrogation of the interplay between the pathogenic variants in multiple genes could improve our understanding of the pathophysiologic pathways and contribute to therapeutic discoveries.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide, with potential causes stemming from obesity, metabolic syndrome, genetic disorders, and drug toxicity. We report a 42-year-old woman with lipodystrophy and NAFLD due to a pathogenic variant in the LMNA (D300N) gene. This case report attempts to encourage clinicians to consider genetic diseases, specifically lipodystrophies, when working up uncommon causes of NAFLD.

BackgroundWe retrospectively reviewed the neuroimaging findings of patients with Cowden syndrome and determined their frequency in a single cohort.MethodsElectronic medical records were queried from January 1999 to January 2017 to identify patients who fit the clinical criteria for diagnosis of Cowden syndrome with or without a documented PTEN mutation. Patients with brain MRI examinations were then identified.ResultsWe retrospectively identified 44 patients with Cowden syndrome, 22 of whom had neuroimaging for review. Eleven (50%) had Lhermitte-Duclos disease, 4 (18.1%) had meningiomas, 13 (59.1%) had at least one developmental venous anomaly, 3 had cavernous malformations, 2 had evidence of dural arteriovenous fistula, 7 had increased white matter signal abnormalities relative to age (31.8%), 4 had prominent perivascular spaces, cerebellar tonsillar ectopia was present in 7 of 21 (33.3%), and 1 had cortical malformation.ConclusionsIt is important to recognize that in addition to Lhermitte-Duclos disease, other intracranial findings such as multiple venous anomalies, meningiomas, greater than expected white matter signal abnormality, prominent perivascular spaces, and cortical malformations may warrant a thorough evaluation for Cowden syndrome in the appropriate clinical setting. We further recommend that this broader spectrum of intracranial abnormalities be considered for addition to the Cowden syndrome diagnostic criteria at the time of next revision.

Background Mutations in the parkin gene (PRKN) are the most commonly identified genetic factors in early onset Parkinson disease (EOPD), with biallelic mutations, resulting in a clinical phenotype. However, normal variation is also common in PRKN, particularly in the form of copy number variation (CNV), challenging interpretation of genetic testing results. Here we report a case of a 29‐year‐old male with EOPD and two deletions in PRKN detected by chromosomal microarray (CMA). Methods The proband was clinically examined by a neurologist for postural instability with frequent falls, bradykinesia, gait freezing with festination, and hypophonia. Chromosomal microarray analysis (CMA) was performed on the proband and his parents using the Affymetrix CytoScan HD microarray. Subsequent fluorescence in situ hybridization (FISH) was performed on the proband and both parents. Results Chromosomal microarray detected the presence of two deletions of PRKN in the proband. Parental CMA analysis was performed to determine the clinical significance of this finding, as well as to demonstrate phase of these deletions. Parental CMA revealed that one deletion was paternally inherited and one deletion was de novo. A custom FISH approach was then successfully used to phase the deletions. Conclusion Chromosomal microarray and fluorescence in situ hybridization analysis of this trio identified two deletions in PRKN occurring in trans, providing a genetic etiology for the clinical diagnosis of EOPD. The determination of inheritance and phase of the deletions was critical to the proper interpretation of these results. These findings highlight the utility of CMA in the detection of clinically relevant CNVs in cases of EOPD, and also serve to emphasize the importance of follow‐up FISH and parental testing.

Klinefelter syndrome is the most frequent chromosomal aneuploidy in males occurring in about 1 in 660 males. Epidemiological studies have demonstrated increased risk of type 1 diabetes and type 2 diabetes in adults with Klinefelter syndrome. There is only one previous report of neonatal diabetes in a patient with Klinefelter syndrome. We report transient neonatal diabetes due to a pathogenic heterozygous variant in KCNJ11 in a male infant with Klinefelter syndrome. A 78-day old male infant was noted to have sustained hyperglycemia with serum glucose ranging between 148 mg/dL (8.2 mmol/L) and 381 mg/dL (21.2 mmol/L) three days after undergoing a complete repair of an atrioventricular defect. Hemoglobin A1c was 6.6%. The patient was born at term with a birth weight of 2.16 kg following a pregnancy complicated by gestational diabetes that was controlled with diet. The patient was initially started on a continuous intravenous insulin drip and subsequently placed on subcutaneous insulin (glargine, human isophane and regular insulin). Insulin was gradually decreased and eventually discontinued at seven months of age. Chromosomal microarray at 11 weeks of age showed XXY and a panel-based, molecular test for neonatal diabetes revealed a pathogenic heterozygous variant c.685G>A (p.Glu229Lys) in KCNJ11. The patient is now 34 months old and continues to have normal fasting and post-prandial glucose and HbA1C levels. The patient will need prospective follow up for assessment of his glycemic status. To our knowledge this is the second reported case of neonatal diabetes in an infant with Klinefelter syndrome and the first due to a mutation in the KCNJ11 in a patient with Klinefelter syndrome.

Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a rare (≈200 patients worldwide), autosomal dominant microvasculopathy (Online Mendelian Inheritance in Man 192315). The neurologic phenotype is severe and characterized by vision loss and progressive neurocognitive decline in the fourth to sixth decades followed by death within 10 years of symptom onset.1 Brain MRI findings are variable and include white matter lesions with or without nodular enhancement, white matter calcifications, and rim-enhancing mass lesions that can be confused with neoplasm.2 Some patients may have systemic features such as Raynaud syndrome, mild liver and kidney dysfunction, hypertension, and anemia.3,4

Moyamoya angiopathy is a rare cerebral vasculopathy characterized by a progressive stenosis of the terminal portion of the internal carotid arteries and the development of abnormal collateral vessels. Children with moyamoya angiopathy become symptomatic because of cerebral ischemic complications, and many patients eventually need revascularization. In most pediatric patients with this disease, the etiology is likely genetic. We aim to report clinical characteristics of a single-center cohort of pediatric patients with moyamoya. We performed a retrospective chart review of patients

PURPOSE: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD). METHODS: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function. RESULTS: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits. CONCLUSION: We significantly broaden the mutational and clinical spectrum ofCTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila. ispartof: GENETICS IN MEDICINE vol:21 issue:12 pages:2723-2733 ispartof: location:United States status: published

Gastrointestinal motility disorders include a spectrum of mild to severe clinical phenotypes that are caused by smooth muscle dysfunction. We investigated the genetic etiology of severe esophageal, gastric, and colonic dysmotility in two unrelated families with autosomal dominant disease presentation. Using exome sequencing, we identified a 2 base pair insertion at the end of the myosin heavy chain 11 (MYH11) gene in all affected members of Family 1 [NM_001040113:c.5819_5820insCA(p.Gln1941Asnfs*91)] and a 1 base pair deletion at the same genetic locus in Proband 2 [NM_001040113:c.5819del(p.Pro1940Hisfs*91)]. Both variants are predicted to result in a similarly elongated protein product. Heterozygous dominant negative MYH11 pathogenic variants have been associated with thoracic aortic aneurysm and dissection while biallelic null alleles have been associated with megacystis microcolon intestinal hypoperistalsis syndrome. This report highlights heterozygous protein-elongating MYH11 variants affecting the SM2 isoforms of MYH11 as a cause for severe gastrointestinal dysmotility, and we hypothesize that the mechanistic pathogenesis of this disease, dominant hypercontractile loss-of-function, is distinct from those implicated in other diseases involving MYH11 dysfunction.

The phosphatase and tensin homolog (PTEN) located at 10q23.31 is a tumor suppressor gene expressed ubiquitously, and loss of function mutations lead to aberrant growth, angiogenesis, and an increased risk for a variety of tumors. PTEN mutations have been associated with multiple abnormalities in the central nervous system, and a number of clinical phenotypes are now attributed to germline PTEN mutations, collectively referred to as PTEN hamartoma tumor syndrome (PHTS). Most notably, these include Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), and autism spectrum disorders with macrocephaly. It is important to recognize the neuroimaging features associated with PTEN mutations to not only avoid misdiagnosis in cases of known PHTS but also to guide genetic testing in patients who do not yet have an established diagnosis. In this review, the central nervous system imaging features of PTEN-related disorders are discussed.

Mitochondrial disorders are caused by nuclear and mitochondrial pathogenic variants leading to defects in mitochondrial function and cellular respiration. Recently, the nuclear-encoded mitochondrial fusion gene MSTO1 (Misato 1) has been implicated in mitochondrial myopathy and ataxia. Here we report on a 30-yr-old man presenting with a maternally inherited NM_018116.3:c.651C>G, p.F217L missense variant as well as a paternally inherited arr[GRCh37] 1q22(155581773_155706887) × 1 deletion encompassing exons 7–14 of MSTO1. His phenotype included muscle weakness, hypotonia, early motor developmental delay, pectus excavatum, and scoliosis. Testing revealed elevated plasma creatine kinase, and electromyogram results were consistent with longstanding generalized myopathy. These phenotypic features overlap well with previously reported patients harboring biallelic MSTO1 variants. Additionally, our patient presents with dysphagia and restrictive lung disease, not previously reported for MSTO1-associated disorders. The majority of patients with disease-associated variants in MSTO1 present with biallelic variants suggesting autosomal recessive inheritance; however, one family has been reported with a single variant and presumed autosomal dominant inheritance. The pattern of inheritance we observed is consistent with the majority of previous reports suggesting an autosomal recessive disorder. We add to our knowledge of the syndrome caused by variants in MSTO1 and provide additional evidence supporting autosomal recessive inheritance. We also describe phenotypic features not reported in previous cases, although further research is needed to confirm they are associated with defects in MSTO1.

OBJECTIVE The aim of this study was to perform an updated review of the imaging features of dysplastic cerebellar gangliocytoma (DCG). METHODS Imaging findings were retrospectively reviewed in 14 patients with DCG. The analysis included size, location, cyst formation, calcification, intralesional hemorrhage, enhancement pattern, and apparent diffusion coefficient (ADC). RESULTS In addition to revisiting many well-established imaging features of DCG, enhancement was much more common (64.3%) than previously reported, and small enhancing veins were also frequently encountered within or along the periphery of the lesions (50%). Dysplastic cerebellar gangliocytomas had an elevated ADC compared with normal cerebellum (967.8 ± 115.7 vs 770.4 ± 47.3 × 10 mm/s; P < 0.0001). CONCLUSIONS Enhancement on magnetic resonance imaging within DCG should be an accepted imaging finding rather than being viewed as uncommon or atypical. Dysplastic cerebellar gangliocytomas typically have an elevated ADC compared with normal cerebellum, which may assist in differentiation from other posterior fossa neoplasms.

International audience; Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels control neuronal excitability and their dysfunction has been linked to epileptogenesis but few individuals with neurological disorders related to variants altering HCN channels have been reported so far. In 2014, we described five individuals with epileptic encephalopathy due to de novo HCN1 variants. To delineate HCN1-related disorders and investigate genotype-phenotype correlations further, we assembled a cohort of 33 unpublished patients with novel pathogenic or likely pathogenic variants: 19 probands carrying 14 different de novo mutations and four families with dominantly inherited variants segregating with epilepsy in 14 individuals, but not penetrant in six additional individuals. Sporadic patients had epilepsy with median onset at age 7 months and in 36% the first seizure occurred during a febrile illness. Overall, considering familial and sporadic patients, the predominant phenotypes were mild, including genetic generalized epilepsies and genetic epilepsy with febrile seizures plus (GEFS+) spectrum. About 20% manifested neonatal/infantile onset otherwise unclassified epileptic encephalopathy. The study also included eight patients with variants of unknown significance: one adopted patient had two HCN1 variants, four probands had intellectual disability without seizures, and three individuals had missense variants inherited from an asymptomatic parent. Of the 18 novel pathogenic missense variants identified, 12 were associated with severe phenotypes and clustered within or close to transmembrane domains, while variants segregating with milder phenotypes were located outside transmembrane domains, in the intracellular N- and C-terminal parts of the channel. Five recurrent variants were associated with similar phenotypes. Using whole-cell patch-clamp, we showed that the impact of 12 selected variants ranged from complete loss-of-function to significant shifts in activation kinetics and/or voltage dependence. Functional analysis of three different substitutions altering Gly391 revealed that these variants had different consequences on channel biophysical properties. The Gly391Asp variant, associated with the most severe, neonatal phenotype, also had the most severe impact on channel function. Molecular dynamics simulation on channel structure showed that homotetramers were not conducting ions because the permeation path was blocked by cation(s) strongly complexed to the Asp residue, whereas heterotetramers showed an instantaneous current component possibly linked to deformation of the channel pore. In conclusion, our results considerably expand the clinical spectrum related to HCN1 variants to include common generalized epilepsy phenotypes and further illustrate how HCN1 has a pivotal function in brain development and control of neuronal excitability.

Exome sequencing is being used increasingly to evaluate patients with intellectual disability. YY1 is a ubiquitously distributed transcription factor belonging to the GLIKruppel class of zinc finger proteins recently recognized as the causative gene in 23 patients for the Gabriele-de Vries syndrome. We report a new case with similar features and a novel variant in YY1, in a region of the gene, which has not previously been reported. A 25 year old female was referred to clinical genetics with a diagnosis of autoimmune myasthenia gravis, facial dysmorphism and learning disability. Chromosomal microarray and gene panel test for congenital myasthenic syndrome was negative. Whole exome sequencing (WES) revealed a presumed pathogenic de novo novel, heterozygous, truncating variant in the YY1 gene, c.860_864delTTAAAA, p.Ile287Argfs*3. The Ile287 residue is conserved across species and is situated in the transcription repressor domain of the protein. This variant is novel and lies in a domain of the protein where no previously reported variants occur. The phenotypic features of our case closely match those of the reported patients. Autoimmune myasthenia gravis has not been reported in these patients and may constitute an expansion of this phenotypic spectrum or perhaps more likely a second unrelated diagnosis.

Next generation sequencing panels have revolutionized the diagnostic approach to patients with epilepsy. There are several commercial epilepsy panels available. We assessed the list of genes tested and consent forms for epilepsy panels available at seven laboratories. The panels varied in the number of genes included (70-465 genes). In some panels, genes not currently associated with epilepsy were included (up to 4 % of panel content). The panels also included genes for lysosomal storage disorders (6-12 %), congenital disorders of glycosylation (0-8.5 %), metabolic disorders (3.5-34 %), neurological syndromes (18-43 %) and multisystemic genetic syndromes (6.4-21 %). Informed consents differed significantly between laboratories ranging from basic information about genetic testing and possible results to information about insurance, genetic counseling and familial testing, and incidental findings.Our findings suggest that it is important to consider the range of genes offered on epilepsy panels and their predicted phenotypes in an effort toward improving the informed consent process.

Background Noonan syndrome with multiple lentigines (NSML), formerly known as LEOPARD syndrome, is an autosomal-dominant disorder characterised by lentigines, EKG abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, growth retardation and deafness. There is significant clinical overlap between NSML and other disorders that result from dysregulated rat sarcoma/mitogen-activated protein kinase pathway (RASopathies). Except for neurofibromatosis type 1, other RASopathies are not known to be typically associated with neurogenic tumours. Methods and results We evaluated patients from three families with pigmentary skin lesions, progressive neuropathy, enlarged nerves, massive burden of paraspinal tumours (neurofibroma was confirmed in one patient) and a clinical diagnosis of NSML. All patients had a mutation in the protein tyrosine phosphatase catalytic domain of the PTPN11 gene; two unrelated patients had the p.Thr468Met mutation, while the family consisting of two affected individuals harboured the p.Thr279Cys mutation. Molecular analysis performed on hypertrophic nerve tissue did not disclose a second somatic hit in NF1, PTPN11, NF2 or SMARCB1 genes. Conclusions Neurogenic tumours and hypertrophic neuropathy are unusual complications of NSML and may be an under-recognised manifestation that would warrant surveillance. Our observation may also have implications for other disorders caused by RAS-pathway dysregulation.

Keywords: chorea; whole-exome sequencing; guanine nucleotide-binding protein; α-activating activity polypeptide O (GNAO1)

Neurofibromatosis type 1 (NF1), one of the most common genetic disorders with an estimated prevalence of 1:3000 live births, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p.Arg1809 and an in-frame 1-amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 patients (129 unrelated probands and 33 affected relatives) carrying a constitutional missense mutation affecting one of five neighboring NF1 codons Leu844, Cys845, Ala846, Leu847 and Gly848, located in the Cysteine-Serine-Rich Domain (CSRD). These recurrent missense mutations affect ~0.8% of unrelated NF1 mutation-positive probands in the UAB cohort. A substantial fraction of these patients presented with a severe phenotype, including plexiform and/or spinal neurofibromas, symptomatic optic pathway gliomas, malignant neoplasms or osseous lesions. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent compared with classic NF1 cohorts (both p

A 13-year-old boy presented to the neurology clinic for evaluation of ataxia and intellectual disability. He was born at term via vaginal delivery after an uncomplicated pregnancy with no perinatal complications. Newborn screening (Virginia, 2012) was normal. He was first noted to be ataxic at age 6 months (when he began to sit with support) and his symptoms gradually worsened over time. He had global developmental delay. He began to sit at 14 months of age and walked at 20 months. He had his first words around age 2 and received physical and speech therapy early on. He had acute worsening of his symptoms at age 8 months in the setting of a flu-like illness and was admitted to a local hospital. Workup at the time was reportedly unrevealing and included a normal CT and a normal brain MRI with contrast. His ataxia remained fairly stable over time without regression. He had several episodes of acute worsening with febrile illnesses. He continued to have learning problems at school.

A 15-year-old boy was referred for evaluation of “weak spells” since early childhood. The frequency of these episodes was on an average once a month, and their duration was variable from 4-6 hours to 1-2 days. There was no correlation to dietary intake, prior physical activity, or time of the day. During these spells, there was no reported pain. He experienced difficulty in standing, walking, climbing stairs, and raising his arms over his head. There were no associated cardiac or respiratory symptoms and no reported speech or swallowing difficulties during these spells. These spells would abort spontaneously, and he would always return to his baseline. The examination during the spells was significant for decreased tone and absent reflexes.

Hartsfield syndrome has been recently reported to be associated with mutations in FGFR1 however, to this date; no familial cases have been reported. In this report, we describe two siblings with Hartsfield syndrome and a novel de novo FGFR1 mutation suggesting gonadal mosaicism. The proband presented at our institution at age 6 years with a clinical diagnosis of Hartsfield syndrome and requesting further genetic evaluation. Previous studies included a normal karyotype, oligonucleotide array, and single gene testing for nonsyndromic holoprosencephaly (SHH, SIX3, ZIC2, TGIF). At the age of 6 years, exome sequencing was performed and a de novo novel missense variant was identified in FGFR1 (coding for fibroblast growth factor-1) on chromosome 8p12: c.1880G>C (p.R627T). Subsequently, a younger sibling was born with the same phenotype (holoprosencephaly, ectrodactyly of bilateral hands and feet and bilateral cleft lip and palate). Targeted sequencing of FGFR1 revealed the identical variant that was previously identified in the proband. To our knowledge this observation is the first documentation of familial recurrence of Hartsfield syndrome. As both parents were negative for the sequence variant in FGFR1 gene by testing peripheral blood samples, this suggests gonadal mosaicism. The frequency of gonadal mosaicism in Hartsfield syndrome is not known however given our case, this possibility should be taken in to consideration for recurrence risk estimation in children of clinically unaffected parents. © 2014 Wiley Periodicals, Inc.

Mitochondrial disorders are caused by nuclear and mitochondrial pathogenic variants leading to defects in mitochondrial function and cellular respiration. Recently, the nuclear-encoded mitochondrial fusion gene MSTO1 (Misato 1) has been implicated in mitochondrial myopathy and ataxia. Here we report on a 30-yr-old man presenting with a maternally inherited NM_018116.3:c.651C>G, p.F217L missense variant as well as a paternally inherited arr[GRCh37] 1q22(155581773_155706887) × 1 deletion encompassing exons 7–14 of MSTO1. His phenotype included muscle weakness, hypotonia, early motor developmental delay, pectus excavatum, and scoliosis. Testing revealed elevated plasma creatine kinase, and electromyogram results were consistent with longstanding generalized myopathy. These phenotypic features overlap well with previously reported patients harboring biallelic MSTO1 variants. Additionally, our patient presents with dysphagia and restrictive lung disease, not previously reported for MSTO1-associated disorders. The majority of patients with disease-associated variants in MSTO1 present with biallelic variants suggesting autosomal recessive inheritance; however, one family has been reported with a single variant and presumed autosomal dominant inheritance. The pattern of inheritance we observed is consistent with the majority of previous reports suggesting an autosomal recessive disorder. We add to our knowledge of the syndrome caused by variants in MSTO1 and provide additional evidence supporting autosomal recessive inheritance. We also describe phenotypic features not reported in previous cases, although further research is needed to confirm they are associated with defects in MSTO1.

a b s t r a c t Objective: To evaluate nocturnal polysomnogram findings in children with suspected symptomatic Chiari type I malformation, correlate them with clinical and magnetic resonance imaging data and to determine if this information has value in clinical decision making process. Methods: A retrospective review identified 24 children with type I Chiari malformation, presumed symp- tomatic who had undergone neurological assessment, cranial magnetic resonance imaging and nocturnal polysomnography. Perimedullary subarachnoid space effacement on the magnetic resonance studies and the magnitude of cerebellar tonsillar descent in relation to the McRae line were correlated with frequency of obstructive or central sleep apnea, number of cortical arousals and evidence of impaired vocal mobility on laryngoscopy. The Wilcoxon rank sum test was applied for continuous variables and the Fisher exact test for categorical variables. Results: The median age of the subjects was 6 years. The findings from 16/24 subjects with perimedullary subarachnoid space effacement (effaced group) were compared with those of 8/24 in the non-effaced group. The central apnea index (1.5 (IQR 1-3.5) versus 0.5 (IQR 0-1.5)) and cortical arousal index (12 (IQR 10-19) versus 8 (IQR 6.5-9)) were significantly higher in the effaced group than in the non-effaced group (p = 0.0376 and 0.0036 respectively). Greater descent of tonsils as measured by distance from the McRae line to the tonsil tip was associated with significantly higher central apnea index, total arousal index and respiratory event related arousals. Measurements of clivus-canal angle, Klauss index and pB-C2 line did not correlate with abnormalities on polysomnography. Conclusion: The central apnea and arousal indices derived from the nocturnal polysomnogram correlate well with magnetic resonance imaging findings of subarachnoid space effacement and degree of ton- sillar herniation. In children with Chiari type I malformation, the nocturnal polysomnogram findings provides important information that aids in the decision making process about proceeding with surgical decompression.