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TRPM3 encodes a transient receptor potential cation channel of the melastatin family, expressed in the central nervous system and in peripheral sensory neurons of the dorsal root ganglia. The recurrent substitution in TRPM3: c.2509G>A, p.(Val837Met) has been associated with syndromic intellectual disability and seizures. In this report, we present the clinical and molecular features of seven previously unreported individuals, identified by exome sequencing, with the recurrent p.(Val837Met) variant and global developmental delay. Other shared clinical features included congenital hypotonia, dysmorphic facial features (broad forehead, deep-set eyes, and down turned mouth), exotropia, and musculoskeletal issues (hip dysplasia, hip dislocation, scoliosis). Seizures were observed in two of seven individuals (febrile seizure in one and generalized tonic–clonic seizures with atonic drops in another), and epileptiform activity was observed in an additional two individuals. This report extends the number of affected individuals to 16 who are heterozygous for the de novo recurrent substitution p.(Val837Met). In contrast with the initial report, epilepsy was not a mandatory feature observed in this series. TRPM3 pathogenic variation should be considered in individuals with global developmental delays, moderate–severe intellectual disability with, or without, childhood-onset epilepsy.

PURPOSE Missense variants clustering in the BTB domain region of RHOBTB2 cause a developmental and epileptic encephalopathy (DEE) with early-onset seizures and severe intellectual disability. METHODS By international collaboration we assembled individuals with pathogenic RHOBTB2 variants and a variable spectrum of neurodevelopmental disorders (NDDs). By western blotting we investigated the consequences of missense variants in vitro. RESULTS In accordance with previous observations, de novo heterozygous missense variants in the BTB domain region led to a severe DEE in 16 individuals. We now identified also de novo missense variants in the GTPase domain in six individuals with apparently more variable neurodevelopmental phenotypes with or without epilepsy. In contrast to variants in the BTB domain region, variants in the GTPase domain do not impair proteasomal degradation of RHOBTB2 in vitro, indicating different functional consequences.Furthermore, we observed bi-allelic splice-site and truncating variants in nine families with variable neurodevelopmental phenotypes, indicating that complete loss of RHOBTB2 is pathogenic as well. CONCLUSION By identifying phenotype-genotype correlations regarding location and consequences of de novo missense variants in RHOBTB2 and by identifying bi-allelic truncating variants, we further delineate and expand the molecular and clinical spectrum of RHOBTB2 related disorders including both autosomal dominant and recessive NDDs.

Objective Pathogenic variants in KCNB1, encoding the voltage-gated potassium channel KV 2.1, are associated with developmental and epileptic encephalopathy (DEE). Previous functional studies on a limited number of KCNB1 variants indicated a range of molecular mechanisms by which variants affect channel function, including loss of voltage sensitivity, loss of ion selectivity, and reduced cell-surface expression. Methods We evaluated a series of 17 KCNB1 variants associated with DEE or other neurodevelopmental disorders (NDDs) to rapidly ascertain channel dysfunction using high-throughput functional assays. Specifically, we investigated the biophysical properties and cell-surface expression of variant KV 2.1 channels expressed in heterologous cells using high-throughput automated electrophysiology and immunocytochemistry-flow cytometry. Results Pathogenic variants exhibited diverse functional defects, including altered current density and shifts in the voltage dependence of activation and/or inactivation, as homotetramers or when coexpressed with wild-type KV 2.1. Quantification of protein expression also identified variants with reduced total KV 2.1 expression or deficient cell-surface expression. Interpretation Our study establishes a platform for rapid screening of KV 2.1 functional defects caused by KCNB1 variants associated with DEE and other NDDs. This will aid in establishing KCNB1 variant pathogenicity and the mechanism of dysfunction, which will enable targeted strategies for therapeutic intervention based on molecular phenotype. ANN NEUROL 2019;86:899-912.

Background: Multiple congenital anomalies-hypotony-seizures syndrome 3 (MCAHS3) is a rare autosomal recessive disorder caused by mutations in the PIGT gene. PIGT encodes phosphatidylinositol-glycan biosynthesis class T, which plays a crucial role in protein anchoring to cell membranes. The clinical presentation of MCAHS3 is variable in expression and severity, but can be characterized by developmental delay, seizures, hypotonia, facial dysmorphism, and other abnormalities.Materials and Methods: Case report.Results: We report unusual ocular findings including bilateral anterior segment dysgenesis, avascular retinal periphery, and tractional retinal detachment in a 1-month-old male infant with compound heterozygous PIGT mutations consistent with MCAHS3. Whole-exome sequencing did not detect any other genetic abnormalities.Conclusions: This case expands the clinical spectrum of MCAHS3 to include anomalies in ocular anterior segment and retinal vascular development. Given the rarity and the genetic heterogeneity of MCAHS3, giving rise to varied non-ocular phenotypes, it is possible that milder intraocular phenotypes could have gone unrecognized in the past.

OBJECTIVE: To investigate the frequency of genetic diagnoses among infants with critical congenital heart disease (CHD) using a comprehensive cardiovascular genetics approach and to identify genotype-phenotype correlations. STUDY DESIGN: A retrospective chart review of patients evaluated by cardiovascular genetics in a pediatric cardiac intensive care unit from 2010 to 2015 was performed. Infants with CHD who were < 1 month of age were included. CHD was classified using structured phenotype definitions. Cardiac and non-cardiac phenotypes were tested for associations with abnormal genetic testing using chi-squared and Fisher’s exact tests. RESULTS: Genetic evaluation was completed in 293 infants with CHD, of whom 213 had isolated CHD (iCHD) and 80 had multiple congenital anomalies (MCA). Overall the yield of abnormal genetic testing was 26%. The MCA cohort had a greater yield of genetic testing (39%) than the iCHD cohort (20%) (odds ratio 2.7). Utilizing a non-hierarchical CHD classification and excluding 22q11.2 deletion and common aneuploidies, right ventricular obstructive defects were associated with abnormal genetic testing (p=0.0005). Extracardiac features associated with abnormal genetic testing included ear, nose and throat (p=0.003) and brain (p=0.0001) abnormalities. A diagnosis of small for gestational age or intrauterine growth retardation was also associated with abnormal genetic testing (p=0.0061), as was presence of dysmorphic features (p=0.0033, odds ratio 3.5). Nondysmorphic infants with iCHD or MCA had similar frequencies of abnormal genetic testing. CONCLUSION: The present study provides evidence to support a comprehensive cardiovascular genetics approach in evaluating infants with critical CHD while also identifying important genotype-phenotype considerations.

Multifocal atrial tachycardia (MAT) has a well-known association with Costello syndrome, but is rarely described with related RAS/MAPK pathway disorders (RASopathies). We report 11 patients with RASopathies (Costello, Noonan, and Noonan syndrome with multiple lentigines [formerly LEOPARD syndrome]) and nonreentrant atrial tachycardias (MAT and ectopic atrial tachycardia) demonstrating overlap in cardiac arrhythmia phenotype. Similar overlap is seen in RASopathies with respect to skeletal, musculoskeletal and cutaneous abnormalities, dysmorphic facial features, and neurodevelopmental deficits. Nonreentrant atrial tachycardias may cause cardiac compromise if sinus rhythm is not restored expeditiously. Typical first-line supraventricular tachycardia anti-arrhythmics (propranolol and digoxin) were generally not effective in restoring or maintaining sinus rhythm in this cohort, while flecainide or amiodarone alone or in concert with propranolol were effective anti-arrhythmic agents for acute and chronic use. Atrial tachycardia resolved in all patients. However, a 4-month-old boy from the cohort was found asystolic (with concurrent cellulitis) and a second patient underwent cardiac transplant for heart failure complicated by recalcitrant atrial arrhythmia. While propranolol alone frequently failed to convert or maintain sinus rhythm, fleccainide or amiodarone, occasionally in combination with propranolol, was effective for RASopathy patient treatment for nonreentrant atrial arrhythmia. Our analysis shows that RASopathy patients may have nonreentrant atrial tachycardia with and without associated cardiac hypertrophy. While nonreentrant arrhythmia has been traditionally associated with Costello syndrome, this work provides an expanded view of RASopathy cardiac arrhythmia phenotype as we demonstrate mutant proteins throughout this signaling pathway can also give rise to ectopic and/or MAT.

Background Joubert syndrome (JS) is a rare, autosomal recessively inherited genetic disorder characterized morphologically by unique developmental malformations of the cerebellum and brainstem (the molar tooth sign), and clinically by impaired motor functions and intellectual disability. Patients with JS often face multiple cognitive challenges, but the neuropsychological profile of this condition has not been well characterized. Methods We performed comprehensive neurological and neuropsychological evaluations in three adult brothers with JS, ages 32, 27, and 25 years. Results They all exhibited impaired motor control, global developmental delay most evident in executive function, affect regulation, and social skill set, and similar patterns of neuropsychiatric symptoms. Conclusions These findings provide new insights into the intellectual and neurobehavioral phenotype of JS, which we regard as a developmental form of the cerebellar cognitive affective / Schmahmann syndrome (CCAS). These observations have direct clinical relevance for the diagnosis and care of patients with JS, and they help further the understanding of the multiple manifestations of atypical cerebrocerebellar development.

The frequent occurrence of congenital heart defects (CHDs) in chromosome abnormality syndromes is well-known, and among aneuploidy syndromes, distinctive patterns have been delineated. We update the type and frequency of CHDs in the aneuploidy syndromes involving trisomy 13, 18, 21, and 22, and in several sex chromosome abnormalities (Turner syndrome, trisomy X, Klinefelter syndrome, 47,XYY, and 48,XXYY). We also discuss the impact of noninvasive prenatal screening (mainly, cell-free DNA analysis), critical CHD screening, and the growth of parental advocacy on their surgical management and natural history. We encourage clinicians to view the cardiac diagnosis as a "phenotype" which supplements the external dysmorphology examination. When detected prenatally, severe CHDs may influence decision-making, and postnatally, they are often the major determinants of survival. This review should be useful to geneticists, cardiologists, neonatologists, perinatal specialists, other pediatric specialists, and general pediatricians. As patients survive (and thrive) into adulthood, internists and related adult specialists will also need to be informed about their natural history and management.

Pathogenic variants inKCNB1, encoding the voltage-gated potassium channel Kv2.1, are associated with developmental and epileptic encephalopathies (DEE). Previous functional studies on a limited number ofKCNB1variants indicated a range of molecular mechanisms by which variants affect channel function, including loss of voltage sensitivity, loss of ion selectivity, and reduced cell-surface expression. We evaluated a series of 17KCNB1variants associated with DEE or neurodevelopmental disorder (NDD) to rapidly ascertain channel dysfunction using high-throughput functional assays. Specifically, we investigated the biophysical properties and cell-surface expression of variant Kv2.1 channels expressed in heterologous cells using high-throughput automated electrophysiology and immunocytochemistry-flow cytometry. Pathogenic variants exhibited diverse functional defects, including altered current density and shifts in the voltage-dependence of activation and/or inactivation, as homotetramers or when co-expressed with wild-type Kv2.1. Quantification of protein expression also identified variants with reduced total Kv2.1 expression or deficient cell-surface expression.Our study establishes a platform for rapid screening of functional defects ofKCNB1variants associated with DEE and other NDDs, which will aid in establishingKCNB1variant pathogenicity and may enable discovery of targeted strategies for therapeutic intervention based on molecular phenotype.

The term 22q11.2 deletion syndrome (22q11DS) includes several clinical syndromes, most notably DiGeorge syndrome and velocardiofacial syndrome (VCFS), whose phenotypes reflect the breadth of phenotype and severity of this syndrome. Cardinal abnormalities include conotruncal heart defects, thymus hypoplasia or aplasia causing cellular immunodeficiency, parathyroid insufficiency with hypocalcemia, and palate defects or velopharyngeal insufficiency. Patients with 22q11DS can have congenital defects and comorbidities in virtually any body system, many of which interfere with sleep.

International audience; N-terminal acetylation is a common protein modification in eukaryotes associated with numerous cellular processes. Inherited mutations in NAA10, encoding the catalytic subunit of the major N-terminal acetylation complex NatA have been associated with diverse, syndromic X-linked recessive disorders, whereas de novo missense mutations have been reported in one male and one female individual with severe intellectual disability but otherwise unspecific phenotypes. Thus, the full genetic and clinical spectrum of NAA10 deficiency is yet to be delineated. We identified three different novel and one known missense mutation in NAA10, de novo in 11 females, and due to maternal germ line mosaicism in another girl and her more severely affected and deceased brother. In vitro enzymatic assays for the novel, recurrent mutations p.(Arg83Cys) and p.(Phe128Leu) revealed reduced catalytic activity. X-inactivation was random in five females. The core phenotype of X-linked NAA10-related N-terminal-acetyltransferase deficiency in both males and females includes developmental delay, severe intellectual disability, postnatal growth failure with severe microcephaly, and skeletal or cardiac anomalies. Genotype–phenotype correlations within and between both genders are complex and may include various factors such as location and nature of mutations, enzymatic stability and activity, and X-inactivation in females.

This review summarizes common microdeletion and microduplication syndromes and highlights important updates in patient-care needs for people with these conditions (22q11.2, 7q11.23, 17p11.2, and 16p11.2). These conditions are in chromosomal “hotspots” and have an estimated prevalence of 1 in 1,000 to 1 in 25,000. Some conditions have possible increased or decreased genetic risk of schizophrenia (22q11.2 deletion and duplication), or risk of aortic dilation (7q11.23 duplication) versus aortic stenosis (7q11.23 deletion). Many of these conditions are associated with developmental delay, autism, and/or multiple congenital anomalies and would not be detected with a karyotype. Chromosomal microarray analysis will detect all these conditions with a single screening test, allowing for the appropriate diagnosis and management of these patients. [ Pediatr Ann. 2018;47(5):e198–e203.]

BackgroundThere is a known high prevalence of genetic and clinical syndrome diagnoses in the paediatric cardiac population. These disorders often have multisystem effects, which may have an important impact on neurodevelopmental outcomes. Taken together, these facts suggest that patients and families may benefit from consultation by genetic specialists in a cardiac neurodevelopmental clinic.ObjectiveThis study assessed the burden of genetic disorders and utility of genetics evaluation in a cardiac neurodevelopmental clinic.MethodsA retrospective chart review was conducted of patients evaluated in a cardiac neurodevelopmental clinic from 6 December, 2011 to 16 April, 2013. All patients were seen by a cardiovascular geneticist with genetic counselling support.ResultsA total of 214 patients were included in this study; 64 of these patients had a pre-existing genetic or syndromic diagnosis. Following genetics evaluation, an additional 19 were given a new clinical or laboratory-confirmed genetic diagnosis including environmental such as teratogenic exposures, malformation associations, chromosomal disorders, and single-gene disorders. Genetic testing was recommended for 112 patients; radiological imaging to screen for congenital anomalies for 17 patients; subspecialist medical referrals for 73 patients; and non-genetic clinical laboratory testing for 14 patients. Syndrome-specific guidelines were available and followed for 25 patients with known diagnosis. American Academy of Pediatrics Red Book asplenia guideline recommendations were given for five heterotaxy patients, and family-based cardiac screening was recommended for 23 families affected by left ventricular outflow tract obstruction.ConclusionGenetics involvement in a cardiac neurodevelopmental clinic is helpful in identifying new unifying diagnoses and providing syndrome-specific care, which may impact the patient’s overall health status and neurodevelopmental outcome.

Noonan Syndrome (NS) is a relatively common genetic disorder with complete penetrance and variable expressivity. More than 80% of NS patients have cardiovascular abnormalities, including malformations and cardiomyopathy. However, the occurrence of left ventricular non compaction (LVNC) in a series of NS patients has not been studied. We present a case series of 6 patients from five families with NS and LVNC. Causative NS mutations were identified in 40% of unrelated patients. LVNC was present as an isolated finding, associated with cardiovascular malformation (CVM), and/ or associated with hypertrophic cardiomyopathy (HCM). This is the first series of LVNC in NS reported. Awareness of NS in LVNC is important for management and family based cardiac screening recommendations.

CHARGE is a well-characterized syndrome (OMIM 2148400) associated with multiple congenital anomalies including cardiovascular malformations. Mutations in CHD7 are the most common cause of CHARGE syndrome. Persistent left superior vena cava (LSVC) has been described in patients with CHARGE syndrome in one study of LSVC associations. A retrospective chart review was conducted for all patients with CHARGE syndrome, diagnosed by Blake criterion features and/or the presence of a pathogenic CHD7 mutation. Echocardio - grams were performed on a clinical basis for all patients and were systematically reviewed and classified. Persistent LSVC was present in 50% of patients with CHARGE syndrome (4/8) and was seen in 3 out of 33 patients seen by cardiovascular genetics with 22q11.2 deletion syndrome. Persistent LSVC is a common finding in patients with CHARGE syndrome and its presence may increase the index of suspicion in patients with other characteristic congenital anomalies.

Deficiency of acid alpha glucosidase (GAA) causes Pompe disease, which is usually fatal if onset occurs in infancy. Patients synthesize a non-functional form of GAA or are unable to form native enzyme. Enzyme replacement therapy with recombinant human GAA (rhGAA) prolongs survival in infantile Pompe patients but may be less effective in cross-reactive immunologic material (CRIM)-negative patients. We retrospectively analyzed the influence of CRIM status on outcome in 21 CRIM-positive and 11 CRIM-negative infantile Pompe patients receiving rhGAA. Patients were from the clinical setting and from clinical trials of rhGAA, were 6 months of age, were not invasively ventilated, and were treated with IV rhGAA at a cumulative or total dose of 20 or 40 mg/kg/2 weeks. Outcome measures included survival, invasive ventilator-free survival, cardiac status, gross motor development, development of antibodies to rhGAA, and levels of urinary Glc(4). Following 52 weeks of treatment, 6/11 (54.5%) CRIM-negative and 1/21 (4.8%) CRIM-positive patients were deceased or invasively ventilated (p

The Professional Practice and Guidelines Committee of the American College of Medical Genetics has the responsibility of overseeing the development of guidelines for the practice of clinical genetics. In the past, most, if not all, guidelines were primarily based on expert opinion. However, recently the goal has become to develop guidelines that are more evidence-based, or at least, to recognize the level of evidence available to the authors of these documents. This article reviews the challenges that are faced by geneticists who are charged with the development of practice guidelines. © 2009 Wiley-Liss, Inc.

The 7q11.23 microduplication syndrome, caused by the reciprocal duplication of the Williams-Beuren syndrome deletion region, is a genomic disorder with an emerging clinical phenotype. Dysmorphic features, congenital anomalies, hypotonia, developmental delay highlighted by variable speech delay, and autistic features are characteristic findings. Congenital heart defects, most commonly patent ductus arteriosus, have been reported in a minority of cases. Included in the duplicated region is elastin (ELN), implicated as the cause of supravalvar aortic stenosis in patients with Williams-Beuren syndrome. Here we present a series of eight pediatric patients and one adult with 7q11.23 microduplication syndrome, all of whom had aortic dilation, the opposite vascular phenotype of the typical supravalvar aortic stenosis found in Williams-Beuren syndrome. The ascending aorta was most commonly involved, while dilation was less frequently identified at the aortic root and sinotubular junction. The findings in these patients support a recommendation for cardiovascular surveillance in patients with 7q11.23 microduplication syndrome.

Introduction Russell–Silver Syndrome (RSS) is a genetically determined condition characterized by severe intrauterine and postnatal growth retardation; relative macrocephaly; a small, triangular face; and fifth-finger clinodactyly. The etiology of RSS involves epigenetic regulation through either uniparental disomy or genomic imprinting via DNA methylation. There has been no documented association between RSS and cardiomyopathy. Methods We present an original case of a 32-year-old woman with RSS with dilated a cardiomyopathy who on cardiac biopsy showed occasional hypertrophic and atrophic myocytes with no evidence of inflammation, abnormal sarcomeres and disintegration of the Z bands on ultrastructural analysis, abnormal desmin, and normal C9 immunoreactivity. Conclusion This case represents the first reported association between RSS and cardiomyopathy. Given the complex mechanisms of disease etiology in RSS, this novel case provides insights into the mechanism of progressive dilated cardiomyopathy in an older individual with RSS.

Adults with 22q11.2 Deletion syndrome (22q11DS) have increased prevalence of schizophrenia features. Our goal is to compare the neurocognitive profile in 22q11DS, schizophrenia and individuals at risk for schizophrenia. Twenty-one 22q11DS patients (8–32 years, mean 14.9 years, 15M, 6F) were matched to four comparison groups on age: low risk (n = 21), first-degree family members of schizophrenia patients (genetic risk, n = 20), individuals exhibiting putatively prodromal symptoms (clinical risk, n = 19), and patients with schizophrenia (n = 21). All participants received semi-structured interviews [Diagnostic Interview for Genetic Studies (DIGS) and the Structured Interview for Prodromal Syndromes (SIPS)], and a computerized neurocognitive battery (CNB) measuring the following domains: Abstraction and Mental Flexibility, Attention, Working Memory, Verbal Memory, Face Memory, Spatial Memory, Language, Spatial Processing, Sensorimotor Dexterity, and Emotion Processing. Sixty percent of 22q11DS participants met SIPS criteria for prodromal symptoms and one participant met criteria for paranoid schizophrenia. Thirty-eight percent met criteria for Depressive Disorders. All 22q11DS participants successfully completed the CNB. 22q11DS participants were significantly less accurate in nearly all domains, but had similar speed of response compared to the other groups. Their profile resembled that of the psychosis groups in accuracy and speed, except for more pronounced deficits in accuracy for face memory and emotion processing. Subthreshold psychotic symptoms are present in a high proportion of 22q11DS participants. Deficits shown in the CNB are more pronounced for accuracy than speed relative to the psychosis groups with similar profiles. Similar deficits have been described in the 22q11DS population using non-computerized measures, which require increased testing time. © 2011 Wiley Periodicals, Inc.

Context Chronic hepatitis C infection (CHCI) is an increasingly common problem, affecting about 2% of the US population. The cost and complexity of treatment and difficulties in communicating with the infected population are of concern to insurers and health planners. Purpose To describe the clinical features of patients with CHCI in a rural Medicaid-covered population and to describe a method developed for treating CHCI in an underserved rural community. Methods We developed a disease management approach to patients with CHCI receiving insurance coverage through a Medicaid HMO in rural Oregon. A locally based multidisciplinary hepatitis committee was formed to develop a management protocol and a process for selecting patients for treatment. The committee met monthly to develop the treatment plan for individual patients. Day-to-day treatment was provided by a nurse under the supervision of the committee. Findings One hundred forty-three adults with CHCI were identified by their primary care physicians. About half the patients had a type 1 genotype. Treatment with pegylated interferon and ribavirin was completed on 21 persons, 11 (52%) of whom had a virologic cure. Problems with treatment toxicity were common. Patient satisfaction with the treatment by the nurse was high. Conclusions CHCI is common in this rural, nonminority Medicaid-insured population. A locally based disease management model was developed that was well received by patients and was successful in delivering a high quality of care for people with CHCI in a rural area.

Leigh syndrome (LS) is a heterogeneous disorder, usually due to a defect in oxidative metabolism. Typically, signs and symptoms commence in infancy or childhood, although rare cases of adult onset have been described. Progressive deterioration is the norm. The authors describe a 22-year-old woman with partial cytochrome c oxidase deficiency who developed fulminant LS following an acute febrile illness and who subsequently showed dramatic clinical and neuroradiologic improvement.

Alstr&ouml, m syndrome is a rare autosomal recessive disorder with dilated cardiomyopathy in 60% of patients. Despite the frequency of cardiac involvement in Alstr&ouml, m syndrome, conduction system abnormalities or arrhythmias have not been characterized previously. We report two siblings with Alstr&ouml, m syndrome with conduction system involvement with left bundle branch block on electrocardiogram (ECG). One patient had first degree atrioventricular block in addition to bundle branch block and underwent pacemaker implantation. This same patient developed intra-atrial reentry tachycardia requiring anti-arrhythmic medication and eventual trans-catheter ablation. The second patient developed atrial and ventricular arrhythmias and underwent placement of a bi-ventricular defibrillator. These findings suggest that cardiac conduction system involvement and clinical arrhythmia may be significant yet under-recognized complications in patients with Alstr&ouml, m syndrome. Patients should be routinely screened with ECG and Holter monitoring in addition to echocardiographic assessment and a cardiologist experienced with cardiomyopathy should be an integral part of the care team.