De novo variants in ATP2B1 lead to neurodevelopmental delay.

Calcium (Ca2+) is a universal second messenger involved in synaptogenesis and cell survival; consequently, its regulation is important for neurons. ATPase plasma membrane Ca2+ transporting 1 (ATP2B1) belongs to the family of ATP-driven calmodulin-dependent Ca2+ pumps that participate in the regulation of intracellular free Ca2+. Here, we clinically describe a cohort of 12 unrelated individuals with variants in ATP2B1 and an overlapping phenotype of mild to moderate global development delay. Additional common symptoms include autism, seizures, and distal limb abnormalities. Nine probands harbor missense variants, seven of which were in specific functional domains, and three individuals have nonsense variants. 3D structural protein modeling suggested that the variants have a destabilizing effect on the protein. We performed Ca2+ imaging after introducing all nine missense variants in transfected HEK293 cells and showed that all variants lead to a significant decrease in Ca2+ export capacity compared with the wild-type construct, thus proving their pathogenicity. Furthermore, we observed for the same variant set an incorrect intracellular localization of ATP2B1. The genetic findings and the overlapping phenotype of the probands as well as the functional analyses imply that de novo variants in ATP2B1 lead to a monogenic form of neurodevelopmental disorder.

Biallelic MED27 variants lead to variable ponto-cerebello-lental degeneration with movement disorders.

MED27 is a subunit of the Mediator multiprotein complex, which is involved in transcriptional regulation. Biallelic MED27 variants have recently been suggested to be responsible for an autosomal recessive neurodevelopmental disorder with spasticity, cataracts and cerebellar hypoplasia. We further delineate the clinical phenotype of MED27-related disease by characterizing the clinical and radiological features of 57 affected individuals from 30 unrelated families with biallelic MED27 variants. Using exome sequencing and extensive international genetic data sharing, 39 unpublished affected individuals from 18 independent families with biallelic missense variants in MED27 have been identified (29 females, mean age at last follow-up 17 ± 12.4 years, range 0.1-45). Follow-up and hitherto unreported clinical features were obtained from the published 12 families. Brain MRI scans from 34 cases were reviewed. MED27-related disease manifests as a broad phenotypic continuum ranging from developmental and epileptic-dyskinetic encephalopathy to variable neurodevelopmental disorder with movement abnormalities. It is characterized by mild to profound global developmental delay/intellectual disability (100%), bilateral cataracts (89%), infantile hypotonia (74%), microcephaly (62%), gait ataxia (63%), dystonia (61%), variably combined with epilepsy (50%), limb spasticity (51%), facial dysmorphism (38%) and death before reaching adulthood (16%). Brain MRI revealed cerebellar atrophy (100%), white matter volume loss (76.4%), pontine hypoplasia (47.2%) and basal ganglia atrophy with signal alterations (44.4%). Previously unreported 39 affected individuals had seven homozygous pathogenic missense MED27 variants, five of which were recurrent. An emerging genotype-phenotype correlation was observed. This study provides a comprehensive clinical-radiological description of MED27-related disease, establishes genotype-phenotype and clinical-radiological correlations and suggests a differential diagnosis with syndromes of cerebello-lental neurodegeneration and other subtypes of 'neuro-MEDopathies'.

Telemedicine Versus Traditional In-Person Consultations: Comparison of Patient Satisfaction Rates.

Introduction: Data on patient satisfaction with the provision of genetic consultations using telemedicine are limited, especially those involving children. We compared patient satisfaction rates with telemedicine services versus traditional in-person encounters. Methods: A cross-sectional questionnaire-based study was conducted between January and June 2020. Questionnaires were distributed online to 1,672 consecutive patients who had received genetic counseling at our Genetics Institute in the clinical fields of adult and pediatric genetics, oncogenetics, and prenatal genetics, through in-person and/or telemedicine consultation. We used Likert scale with scores of 4-5 representing "satisfied"-"very satisfied" and 1-2 representing "very unsatisfied"-"unsatisfied." Results: The response rate was 27.3% (400 adults and 57 children <18 years), including 330 who had received in-person consultations (72.2%), 80 telemedicine consultations (17.5%), and 47 both consultations (10.3%). Mean satisfactory scores of 4-5 were reported by 82.1% in the in-person group versus 82.5% in the telemedicine group (p = 0.88). Mean scores of 1-2 were reported by 6.3% in the in-person group versus 11.2% in the telemedicine group (p = 0.31). No pediatric telemedicine group patient (n 12 = ) gave scores of 1-2 compared with 2/33 (6%) patients who had in-person pediatric consultations (p = 0.62). Most responders who had been counseled through telemedicine (n = 127, 84%) indicated willingness to use genetic services through telemedicine again. Conclusions: Users of genetic counseling through telemedicine, especially in the pediatric age group, were very satisfied at rates comparable to those of in-person consultations. Future research should evaluate patient compliance and views according to session type, information provided (e.g., diagnostic vs. negative results), and its nature (good vs. bad news).

Concomitant variants in NF1, LZTR1 and GNAZ genes probably contribute to the aggressiveness of plexiform neurofibroma and warrant treatment with MEK inhibitor.

Neurofibromatosis 1 (NF1) is caused by germline mutations in the NF1 gene and manifests as proliferation of various tissues, including plexiform neurofibromas. The plexiform neurofibroma phenotype varies from indolent to locally aggressive, suggesting contributions of other modifiers in addition to somatic loss of NF1. In this study, we investigated a life-threatening plexiform neurofibroma in a 9-month-old female infant with NF1. Germline mutations in two RASopathy-associated genes were identified using whole-exome sequencing-a de novo pathogenic variant in the NF1 gene, and a known pathogenic variant in the LZTR1 gene. Somatic analysis of the plexiform neurofibroma revealed NF1 loss of heterozygosity and a variant in GNAZ, a gene encoding a G protein-coupled receptor. Cells expressing mutant GNAZ exhibited increased ERK 1/2 activation compared to those expressing wild-type GNAZ. Taken together, we suggest the variants in NF1, LZRT1 and GNAZ act synergistically in our patient, leading to MAPK pathway activation and contributing to the severity of the patient's plexiform neurofibromatosis. After treatment with the MEK inhibitor, trametinib, a prominent clinical improvement was observed in this patient. This case study contributes to the knowledge of germline and somatic non-NF1 variants affecting the NF1 clinical phenotype and supports use of personalized, targeted therapy.

SCN3A-Related Neurodevelopmental Disorder: A Spectrum of Epilepsy and Brain Malformation.

OBJECTIVE: Pathogenic variants in SCN3A, encoding the voltage-gated sodium channel subunit Nav1.3, cause severe childhood onset epilepsy and malformation of cortical development. Here, we define the spectrum of clinical, genetic, and neuroimaging features of SCN3A-related neurodevelopmental disorder. METHODS: Patients were ascertained via an international collaborative network. We compared sodium channels containing wild-type versus variant Nav1.3 subunits coexpressed with ß1 and ß2 subunits using whole-cell voltage clamp electrophysiological recordings in a heterologous mammalian system (HEK-293T cells). RESULTS: Of 22 patients with pathogenic SCN3A variants, most had treatment-resistant epilepsy beginning in the first year of life (16/21, 76%; median onset, 2 weeks), with severe or profound developmental delay (15/20, 75%). Many, but not all (15/19, 79%), exhibited malformations of cortical development. Pathogenic variants clustered in transmembrane segments 4 to 6 of domains II to IV. Most pathogenic missense variants tested (10/11, 91%) displayed gain of channel function, with increased persistent current and/or a leftward shift in the voltage dependence of activation, and all variants associated with malformation of cortical development exhibited gain of channel function. One variant (p.Ile1468Arg) exhibited mixed effects, with gain and partial loss of function. Two variants demonstrated loss of channel function. INTERPRETATION: Our study defines SCN3A-related neurodevelopmental disorder along a spectrum of severity, but typically including epilepsy and severe or profound developmental delay/intellectual disability. Malformations of cortical development are a characteristic feature of this unusual channelopathy syndrome, present in >75% of affected individuals. Gain of function at the channel level in developing neurons is likely an important mechanism of disease pathogenesis. ANN NEUROL 2020;88:348-362.

The phenotype of 15 cases with rare 8q24.13-q24.3 deletions-A new syndrome or still an enigma?

Diagnosis of rare copy number variants (CNVs) with scarce literature evidence poses a major challenge for interpretation of the clinical significance of chromosomal microarray analysis (CMA) results, especially in the prenatal setting. Bioinformatic tools can be used to assist in this issue; however, this prediction can be imprecise. Our objective was to describe the phenotype of the rare copy number losses encompassing the 8q24.13-q24.3 locus, and to find common features in terms of genomic coordinates, gene content, and clinical phenotypic characteristics. Appropriate cases were retrieved using local databases of two largest Israeli centers performing CMA analysis. In addition, literature and public databases search was performed. Local database search yielded seven new patients with del (8)(q24.13q24.3) (one of these with an additional copy number variant). Literature and public databases search yielded eight additional patients. The cases showed high phenotypic variability, ranging from asymptomatic adults and fetuses with normal ultrasound to patients with autism/developmental delay (6/11 postnatal cases, 54.5%). No clear association was noted between the specific disease-causing/high-pLI gene content of the described del (8)(q24.13q24.3) to neurodevelopmental disorders, except for a possibly relevant locus encompassing the KCNQ3 gene. We present the challenges in classification of rare variants with limited clinical information. In such cases, genotype-phenotype correlation must be assessed with extra-caution and possibly using additional methods to assist the classification, especially in the prenatal setting.

Teaching clinicians practical genomic medicine: 7 years' experience in a tertiary care center.

PURPOSE: Increased implementation of complex genetic technologies in clinical practice emphasizes the urgency of genomic literacy and proficiency for medical professionals. We evaluated our genomic education model. METHODS: We assessed the 5-day, extended format program, encompassing lectures, videos, interactive tests, practice cases, and clinical exercises. Pre- and post questionnaires assessed knowledge change, using t-tests to compare groups. Satisfaction on program completion and after 3 years were evaluated. Implementation in other centers determined acceptability. RESULTS: During 2012-2018, 774 clinicians from multiple disciplines and career stages attended 35 programs; 334 (43%) attended the 5-day extended format. Evaluations showed significant improvement of genomic literacy (mean 15.05/100 points, p < 0.001). Residents initially had higher scores than specialists (pre: 66.3 ± 17.3 vs. 58.7 ± 16.6, respectively, p = 0.002); both significantly improved, with specialists "catching up" (post: 79.1 ± 17.2 vs. 75.7 ± 15.9, nonsignificant (NS)); there was a similar trend between fellows and subspecialists (pre: 70 ± 18 vs. 59.4 ± 16.4, respectively, p = 0.007; post: 78.6 ± 16.4 vs. 73.2 ± 17.7, respectively, NS). Younger specialists (≤10 years residency) had significantly higher pre- and post scores. Absolute improvement in scores did not depend on medical specialties. CONCLUSION: Our program is effective in improving genomics literacy for clinicians, irrespective of career length or expertise, and could be a model for improving skills in practical genomics for all medical professionals.

Genetics of tuberous sclerosis complex: an update.

PURPOSE: To review the current genetic aspects of tuberous sclerosis complex. METHODS: Review of the literature. RESULTS: Tuberous sclerosis complex (TSC), a long known childhood-onset monogenic disorder, characterized by hamartoma formation affecting mainly the brain, heart, kidney, lung, and skin, is associated with a high morbidity burden and risk of a reduced life span. The identification of TSC1 and TSC2, as tumor suppressor genes causative of the disorder, led to the elucidation of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway and its pivotal role in the pathogenesis of hamartoma formation. This knowledge was translated into standard clinical practice with the discovery of rapamycin, and additional analogues, as inhibitors of mTORC1. CONCLUSION: Next-generation sequencing was proven to be fundamental to drive research of tumorigenesis in TSC, hopefully leading to new therapeutic options in the future.

[TRMU MUTATIONS - REVERSIBLE INFANTILE LIVER FAILURE OR MULTISYSTEM DISORDER?]

INTRODUCTION: Bi-allelic mutations in the TRMU gene cause reversible infantile liver failure. Little is known about extra-hepatic manifestations in these patients. BACKGROUND: Two infants, aged 4 and 5 months, presented with progressive life threatening liver failure, characterized by lactic acidosis, highly elevated alpha-fetoprotein and recurrent hypoglycemia. Both showed significant extra-hepatic findings, including: hypothyroidism, macrocytic anemia and microcephaly. Both were of Jewish Yemenite descent and homozygous for Y77H mutation in the TRMU gene. CONCLUSIONS: TRMU bi-allelic mutations cause severe life-threatening liver failure. Extra-hepatic involvement is common and should be evaluated. Spontaneous resolution and recovery occurs in most patients with a remarkably good long-term prognosis. Liver failure in a Jewish-Yemenite infant should prompt early genetic testing for TRMU Y77H mutation. Pediatricians should be aware of this disease and the common mutation in Israel. DISCUSSION: Nineteen additional patients were described in the literature, of whom 13 were from Israel; 6/19 (31%) manifested extra-hepatic involvement, namely: myopathic weakness, cardiomyopathy, renomegaly and proteinuria, bulbar dysfunction, cerebral white matter changes and abnormal growth including microcephaly. Mortality was 24% (5/21). Survivors (16/21, 76%) showed complete recovery and resolution of clinical, laboratory and histologic abnormalities. Most Israeli patients (10/15) were of Jewish-Yemenite ancestry. Homozygous Y77H genotype was exclusive to this patient subgroup and was associated with a 100% survival and recovery rate.

Is one diagnosis the whole story? patients with double diagnoses.

One of the goals of evaluating a patient in the genetics clinic is to find the diagnosis that would explain his or her clinical presentation. Sometimes the patient's diagnosis remains undefined or does not explain all of the clinical findings. As clinicians are often guided by a "single disorder" paradigm, diagnosing multiple genetic conditions in the same patient requires a heightened sense of awareness. Over the last few years, we evaluated several patients (n = 14) who were found to have more than one genetic diagnosis. In this paper, we will describe their natural history and diagnoses, and draw on the lessons learned from this phenomenon, which we expect to grow in this era of next-generation diagnostic technologies. To our knowledge, this is by far the largest series of patients with double diagnoses. Based on our findings, we strongly recommend that physicians question every diagnosis to determine whether it indeed explains all of the patients' symptoms, and consider whether they should continue the diagnostic evaluation to look for a more accurate and complete set of diagnoses. © 2016 Wiley Periodicals, Inc.