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Abstract Background Autism spectrum disorders (ASD) represent a group of neurodevelopmental disorders characterized by a core set of social-communicative and behavioral impairments. Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain, acting primarily via the GABA receptors (GABR). Multiple lines of evidence, including altered GABA and GABA receptor expression in autistic patients, indicate that the GABAergic system may be involved in the etiology of autism. Methods As copy number variations (CNVs), particularly rare and de novo CNVs, have now been implicated in ASD risk, we examined the GABA receptors and genes in related pathways for structural variation that may be associated with autism. We further extended our candidate gene set to include 19 genes and regions that had either been directly implicated in the autism literature or were directly related (via function or ancestry) to these primary candidates. For the high resolution CNV screen we employed custom-designed 244 k comparative genomic hybridization (CGH) arrays. Collectively, our probes spanned a total of 11 Mb of GABA-related and additional candidate regions with a density of approximately one probe every 200 nucleotides, allowing a theoretical resolution for detection of CNVs of approximately 1 kb or greater on average. One hundred and sixty-eight autism cases and 149 control individuals were screened for structural variants. Prioritized CNV events were confirmed using quantitative PCR, and confirmed loci were evaluated on an additional set of 170 cases and 170 control individuals that were not included in the original discovery set. Loci that remained interesting were subsequently screened via quantitative PCR on an additional set of 755 cases and 1,809 unaffected family members. Results Results include rare deletions in autistic individuals at JAKMIP1, NRXN1, Neuroligin4Y, OXTR, and ABAT. Common insertion/deletion polymorphisms were detected at several loci, including GABBR2 and NRXN3. Overall, statistically significant enrichment in affected vs. unaffected individuals was observed for NRXN1 deletions. Conclusions These results provide additional support for the role of rare structural variation in ASD.

Acute liver failure is rare in the neonatal and infant population; however, when encountered, it requires timely diagnosis, management, and identification of the underlying etiology to provide the best clinical outcomes. Here, we present a case of new-onset liver failure in a 4-month-old infant. She had previously been diagnosed with neonatal mucocutaneous herpes simplex virus disease, but had been healthy in the interval, and was referred to our hospital for evaluation of possible need for liver transplantation because of a rapidly progressing pace of disease. In this diagnostic dilemma article, we review the case history and presentation and consider the differential diagnosis from the points of view of the primary and consultative teams. We then follow the clinical evolution of disease, identify a final diagnosis, and explore the short- and long-term management and health implications of the diagnosis. This case should be of interest to primary care providers, intensivists who care for neonates or infants, and specialists who encounter liver failure in their clinical practice., (Copyright © 2024 by the American Academy of Pediatrics.)

Newborn screening for Phenylketonuria (PKU) began in 1963, and since then knowledge and treatment recommendations have evolved. In the decades following newborn screening for PKU, individual and family experiences varied widely. We present narratives by people living with PKU during these years, including individuals actively following in PKU clinic and those who have been out of PKU clinic for many years. These stories describe different individual experiences, including diet discontinuation in childhood, changing treatment guidelines, and new treatments that have become available., (© 2024 The Author(s). American Journal of Medical Genetics Part C: Seminars in Medical Genetics published by Wiley Periodicals LLC.)

The understanding of phenylketonuria (PKU), guidelines, and treatment landscape have evolved dramatically over the decades since newborn screen implementation. We capture this rich history from the stories and experiences of a multidisciplinary provider team from Boston Children's Hospital's PKU Clinic, who treated PKU from the early years of newborn screening and who worked together for over 40 years., (© 2024 The Author(s). American Journal of Medical Genetics Part C: Seminars in Medical Genetics published by Wiley Periodicals LLC.)

Over fifty years have passed since the last large scale longitudinal study of individuals with PAH deficiency in the U.S. Since then, there have been significant changes in terms of treatment recommendations as well as treatment options. The Phenylalanine Families and Researchers Exploring Evidence (PHEFREE) Consortium was recently established to collect a more up-to-date and extensive longitudinal natural history in individuals with phenylketonuria across the lifespan. In the present paper, we describe the structure and methods of the PHEFREE longitudinal study protocol and report cross-sectional data from an initial sample of 73 individuals (5 months to 54 years of age) with PAH deficiency who have enrolled. Looking forward, the study holds the promise for advancing the field on several fronts including the validation of novel neurocognitive tools for assessment in individuals with PKU as well as evaluation of the long-term effects of changes in metabolic control (e.g., effects of Phe-lowering therapies) on outcome., Competing Interests: Declaration of competing interest SEC has received consulting fees from BioMarin, Jnana, and PTC; and BioMarin has funded past and current research. GA has served as a consultant for PTC Therapeutics. DKG has conducted clinical research trials for BioMarin and Synlogic related to the treatment of PAH deficiency. COH has received consulting fees from BioMarin, Jnana Therapeutics, PTC Therapeutics, Sanofi, Pfizer, Synlogic, Tessera Therapeutics, and Tome Biosciences and conducted clinical research trials for BioMarin, Jnana Therapeutics, Sanofi, and Synlogic related to treatment of PAH deficiency. EJ has served as a consultant for Jnana Therapeutics, Arcturus Therapeutics, Travere Therapeutics, and participated in advisory boards for Jnana Therapeutics and Sanofi. HL has received consulting fees from BioMarin, Sanofi, Jnana, PTC, and Tome Biosciences. NL has served on advisory boards for Amgen/Horizon, Amicus Therapeutics, Audentes/Astrellas, BioMarin, Chiesi/Protalix, Sanofi, Ipsen, Jaguar Gene Therapy, Jnana, Leadiant Biosciences, Moderna, Nestlé Pharma, PTC Therapeutics, Reneo, and Ultragenyx and has received clinical trial support from Amgen/Horizon, Amicus Therapeutics, Audentes/Astrellas, BioMarin, Chiesi/Protalix, Sanofi, Jnana, Moderna, PTC Therapeutics, Takeda, and Ultragenyx. SS has served on advisory boards and received clinical trial support from BioMarin, Synlogic, PTC Therapeutics, and Jnana Therapeutics. JT has served as a consultant for BioMarin and has received clinical trials support from PTC Therapeutics, BioMarin, and Sanofi. DAW has received clinical trial support from BioMarin., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: Epigenetic dysregulation has been associated with many inherited disorders. RBBP5 (HGNC:9888) encodes a core member of the protein complex that methylates histone 3 lysine-4 and has not been implicated in human disease., Methods: We identify 5 unrelated individuals with de novo heterozygous variants in RBBP5. Three nonsense/frameshift and 2 missense variants were identified in probands with neurodevelopmental symptoms, including global developmental delay, intellectual disability, microcephaly, and short stature. Here, we investigate the pathogenicity of the variants through protein structural analysis and transgenic Drosophila models., Results: Both missense p.(T232I) and p.(E296D) variants affect evolutionarily conserved amino acids located at the interface between RBBP5 and the nucleosome. In Drosophila, overexpression analysis identifies partial loss-of-function mechanisms when the variants are expressed using the fly Rbbp5 or human RBBP5 cDNA. Loss of Rbbp5 leads to a reduction in brain size. The human reference or variant transgenes fail to rescue this loss and expression of either missense variant in an Rbbp5 null background results in a less severe microcephaly phenotype than the human reference, indicating both missense variants are partial loss-of-function alleles., Conclusion: Haploinsufficiency of RBBP5 observed through de novo null and hypomorphic loss-of-function variants is associated with a syndromic neurodevelopmental disorder., Competing Interests: Conflict of Interest The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing conducted at Baylor Genetics Laboratories., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Phenylketonuria (PKU) is a genetic disorder caused by deficiency of the enzyme phenylalanine hydroxylase (PAH), which results in phenylalanine (Phe) accumulation in the blood and brain, and requires lifelong treatment to keep blood Phe in a safe range. Pegvaliase is an enzyme-substitution therapy approved for individuals with PKU and uncontrolled blood Phe concentrations (>600 μmol/L) despite prior management. Aggregated results from the PRISM clinical trials demonstrated substantial and sustained reductions in blood Phe with a manageable safety profile, but also noted individual variation in time to and dose needed for a first response. This analysis reports longer-term aggregate findings and characterizes individual participant responses to pegvaliase using final data from the randomized trials PRISM-1 (NCT01819727) and PRISM-2 (NCT01889862), and the open-label extension study 165-304 (NCT03694353). In 261 adult participants with a mean of 36.6 months of pegvaliase treatment, 71.3%, 65.1%, and 59.4% achieved clinically significant blood Phe levels of ≤600, ≤360, and ≤ 120 μmol/L, respectively. Some participants achieved blood Phe reductions with <20 mg/day pegvaliase, although most required higher doses. Based on Kaplan-Meier analysis, median (minimum, maximum) time to first achievement of a blood Phe threshold of ≤600, ≤360, or ≤ 120 μmol/L was 4.4 (0.0, 54.0), 8.0 (0.0, 57.0), and 11.6 (0.0, 66.0) months, respectively. Once achieved, blood Phe levels remained below clinical threshold in most participants. Sustained Phe response (SPR), a new method described within for measuring durability of blood Phe response, was achieved by 85.5%, 84.7%, and 78.1% of blood Phe responders at blood Phe thresholds of ≤600, ≤360, or ≤ 120 μmol/L, respectively. Longer-term safety data were consistent with previous reports, with the most common adverse events (AEs) being arthralgia, injection site reactions, headache, and injection site erythema. The incidence of most AEs, including hypersensitivity AEs, was higher during the early treatment phase (≤6 months) than later during treatment. In conclusion, using data from three key pegvaliase clinical trials, participants treated with pegvaliase were able to reach clinically significant blood Phe reductions to clinical thresholds of ≤600, ≤360, or ≤ 120 μmol/L during early treatment, with safety profiles improving from early to sustained treatment. This study also supports the use of participant-level data and new ways of looking at durable blood Phe responses to better characterize patients' individual PKU treatment journeys., Competing Interests: COH has received consulting and speaker fees from BioMarin and has participated as a clinical trial investigator for BioMarin. NL has received consulting fees from BioMarin, PTC Therapeutics, Moderna, and Nestlé; speaker fees from Recordati; travel support from BioMarin and Sanofi; and has participated as a clinical trial investigator for BioMarin, PTC Therapeutics, Moderna, Nestlé, and Homology Medicines. HN has participated as a clinical trial investigator for BioMarin, Synlogic, Jnana Therapeutics, Sanofi, and PTC Therapeutics; has received consulting fees from BioMarin, Synlogic, Jnana Therapeutics, and PTC Therapeutics; and has received speaker's fees from BioMarin. SS has participated as a clinical trial investigator for BioMarin, Synlogic, and PTC Therapeutics and received funding for investigator-initiated research from BioMarin. SS also reports participation in advisory boards for BioMarin (without personal compensation since 2018) and paid speaker engagement. RS has participated as a clinical trial investigator, received grant funding, and funding for investigator-initiated research from BioMarin. JT has participated as a clinical trial investigator and advisory board member for BioMarin. JV has received consulting fees from BioMarin, LogicBio Therapeutics, Sangamo Therapeutics, Orphan Lab, Synlogic, Sanofi, Axcella Health, Agios Pharmaceuticals, and Applied Therapeutics, and has received travel grants from BioMarin and LogicBio Therapeutics. RTZ is a consultant for BioMarin and is a principal investigator for Synlogic and PTC Therapeutics. KBW, JL, KL, and DGL are employees of BioMarin Pharmaceutical Inc. SJ is an employee of BioMarin UK. BKB has received consulting fees and/or honoraria from Agios Pharmaceuticals, Aro, BioMarin, Chiesi, Horizon Therapeutics, JCR Pharmaceuticals, Maze Therapeutics, Moderna, Orchard Therapeutics, Passage Bio, Sanofi, Takeda, Travere Therapeutics, and Ultragenyx, and has conducted clinical trials funded by BioMarin, Denali Therapeutics, Homology Medicines, JCR Pharmaceuticals, Sangamo Therapeutics, Takeda, and Ultragenyx., (© 2024 Published by Elsevier Inc.)

Background: Pegvaliase has allowed many adults with phenylketonuria (PKU) to achieve acceptable blood Phe control while eating an unrestricted diet. However, little is known about potential differences in nutritional status and eating behaviors after transitioning from a phenylalanine (Phe)-restricted to an unrestricted diet. Here we assessed change in nutritional status in adults with early-treated PKU who were consuming a Phe-restricted diet (intact protein ≤0.8 g/kg/day) prior to starting pegvaliase., Methods: A 15-month, prospective, longitudinal study to assess change in anthropometrics, dietary intake, laboratory indices of nutritional status, bone mineral density (BMD), body composition, measured resting energy expenditure (REE), and eating behaviors between baseline and Month 15., Results: Eleven adults ( n  = 7 female) aged 19.5-52.9 years completed the study. Six participants had a substantial blood Phe reduction (responders) and five participants had a modest blood Phe reduction (partial responders) by Month 15. Intact protein intake increased by an average of 49.4 g/day and 26.7 g/day in responders and partial responders, respectively. Plasma concentrations of most vitamins, minerals, and essential fatty acids assessed were normal, though micronutrient intakes decreased as participants decreased or discontinued PKU medical food(s). Responders had a more variable change in body mass index (BMI) and lean mass index (LMI) compared to partial responders, though there were no clear trends in BMD or body composition changes. Total protein intake was positively correlated with LMI. Responders, but not partial responders, self-reported increased in enjoyment of food and decreased food neophobia, uncontrolled eating, and emotional eating., Discussion: Participants transitioning to an unrestricted diet while on pegvaliase maintained adequate nutritional status overall with no clinically significant changes in cardiovascular or glycemic markers. Responders reported improvements in eating behaviors, including reduced food neophobia, uncontrolled eating, and emotional eating, and increased enjoyment of food. There were no consistent trends in BMD, body composition, or BMI changes. A larger sample size and longer follow-up period are needed to further assess potential changes., Competing Interests: None.

Sengers syndrome (OMIM# 212350) is a rare autosomal recessive mitochondrial disease caused by biallelic pathogenic variants in the AGK gene, which encodes the acylglycerol kinase enzyme. The syndrome was originally defined as a "triad" of hypertrophic cardiomyopathy, cataracts, and lactic acidosis, with or without skeletal myopathy. The clinical manifestation of Sengers Syndrome exhibits substantial heterogeneity, with mild and severe/infantile forms reported. Further, biallelic AGK pathogenic variants have also been identified in a familial case of non-syndromic isolated cataract (OMIM# 614691), expanding our understanding of the gene's influence beyond the originally defined syndrome. In this study, we provide a systematic review of molecularly confirmed cases with biallelic AGK pathogenic variants (Supplementary Table 1). Our analysis demonstrates the variable expressivity and penetrance of the central features of Sengers syndrome, as follows: cataracts (98%), cardiomyopathy (88%), lactic acidosis (adjusted 88%), and skeletal myopathy (adjusted 74%) (Table 1). Furthermore, we investigate the associations between genotype, biochemical profiles, and clinical outcomes, with a particular focus on infantile mortality. Our findings reveal that patients carrying homozygous nonsense variants have a higher incidence of infant mortality and a lower median age of death (p = 0.005 and p = 0.02, Table 2a). However, the location of pathogenic variants within the AGK domains was not significantly associated with infantile death (p = 0.62, Table 2b). Additionally, we observe a borderline association between the absence of lactic acidosis and longer survival (p = 0.053, Table 2c). Overall, our systematic review sheds light on the diverse clinical manifestations of AGK-related disorders and highlights potential factors that influence its prognosis. These provide important implications for the diagnosis, treatment, and counseling of affected individuals and families., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

Purpose: LHX2 encodes the LIM homeobox 2 transcription factor (LHX2), which is highly expressed in brain and well conserved across species, but it has not been clearly linked to neurodevelopmental disorders (NDDs) to date., Methods: Through international collaboration, we identified 19 individuals from 18 families with variable neurodevelopmental phenotypes, carrying a small chromosomal deletion, likely gene-disrupting or missense variants in LHX2. Functional consequences of missense variants were investigated in cellular systems., Results: Affected individuals presented with developmental and/or behavioral abnormalities, autism spectrum disorder, variable intellectual disability, and microcephaly. We observed nucleolar accumulation for 2 missense variants located within the DNA-binding HOX domain, impaired interaction with co-factor LDB1 for another variant located in the protein-protein interaction-mediating LIM domain, and impaired transcriptional activation by luciferase assay for 4 missense variants., Conclusion: We implicate LHX2 haploinsufficiency by deletion and likely gene-disrupting variants as causative for a variable NDD. Our findings suggest a loss-of-function mechanism also for likely pathogenic LHX2 missense variants. Together, our observations underscore the importance of LHX2 in the nervous system and for variable neurodevelopmental phenotypes., Competing Interests: Conflict of Interest A.O.-L. is a paid member of the Scientific Advisory Board of SPARK for Autism. M.P.N., K.Mon., and T.B.P. are employees of GeneDx, LLC. All other authors declare no conflicts of interest., (Copyright © 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Novel pharmaceutical therapies such as pegvaliase, phenylalanine ammonia lyase (PAL), have enhanced disease control for many individuals with phenylketonuria (PKU). We present a retrospective chart review to assess pegvaliase doses over time in individuals followed at the Boston Children's Hospital PAL Clinic, including those who started pegvaliase in a clinical trial ("trial patients") and those who started after drug came to market ("post-market patients"). Trial patients were on pegvaliase an average of 4.8 years longer, and their mean current pegvaliase dose was 126 ± 92 compared to 223 ± 147 mg/week for post-market patients (p = 0.0155), suggesting that the pegvaliase dose for target efficacy may decrease over time in adults with PKU. In post-market patients, we demonstrated a significant, inverse correlation with dose change and number of weeks from response (r = -0.46, p = 0.046). The entire cohort showed significant variability in terms of time to achieve a therapeutic response, response dose, and current dose. Our data suggest that patients tolerate a reduction in pegvaliase dose over time while maintaining efficacy. This is a clinically meaningful finding as it indicates that patients may reduce number of weekly injections over time on pegvaliase., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Early treated patients with phenylketonuria (PKU) often become lost to follow-up from adolescence onwards due to the historical focus of PKU care on the pediatric population and lack of programs facilitating the transition to adulthood. As a result, evidence on the management of adolescents and young adults with PKU is limited., Methods: Two meetings were held with a multidisciplinary international panel of 25 experts in PKU and comorbidities frequently experienced by patients with PKU. Based on the outcomes of the first meeting, a set of statements were developed. During the second meeting, these statements were voted on for consensus generation (≥70% agreement), using a modified Delphi approach., Results: A total of 37 consensus recommendations were developed across five areas that were deemed important in the management of adolescents and young adults with PKU: (1) general physical health, (2) mental health and neurocognitive functioning, (3) blood Phe target range, (4) PKU-specific challenges, and (5) transition to adult care. The consensus recommendations reflect the personal opinions and experiences from the participating experts supported with evidence when available. Overall, clinicians managing adolescents and young adults with PKU should be aware of the wide variety of PKU-associated comorbidities, initiating screening at an early age. In addition, management of adolescents/young adults should be a joint effort between the patient, clinical center, and parents/caregivers supporting adolescents with gradually gaining independent control of their disease during the transition to adulthood., Conclusions: A multidisciplinary international group of experts used a modified Delphi approach to develop a set of consensus recommendations with the aim of providing guidance and offering tools to clinics to aid with supporting adolescents and young adults with PKU., Competing Interests: Declaration of competing interest The content of this manuscript was based on preparatory pre-meeting activities and presentations and discussions during two advisory board meetings that were coordinated and funded by BioMarin Pharmaceutical Inc. All authors or their institutions received funding from BioMarin to attend at least one or both meetings. Additional disclosures: BKB received consulting payments from BioMarin, Shire, Genzyme, Alexion, Horizon Therapeutics, Denali Therapeutics, JCR Pharma, Moderna, Aeglea BioTherapeutics, SIO Gene Therapies, Taysha Gene Therapy, Ultragenyx, and Inventiva Pharma, participated as clinical trial investigator for BioMarin, Shire, Denali Therapeutics, Homology Medicines, Ultragenyx, and Moderna as well as received speaker fees from BioMarin, Shire, Genzyme, and Horizon Therapeutics. AH received consulting payments from BioMarin, Chiesi, Shire, Genzyme, Amicus, and Ultragenyx, participated as clinical trial investigator for Ultragenyx as well as received speaker fees from Alexion, Amicus, BioMarin, Genzyme, Nutricia, Sobi, and Takeda. ABQ received consulting payments from BioMarin, speaker fees from BioMarin, Nutricia, Vitaflo, Sanofi, Takeda, Recordati, and travel support from Vitaflo. SEC received consulting payments and speaker fees from BioMarin as well as consulting payments from Synlogic Therapeutics. COH was clinical trial investigator for BioMarin and received consulting and speaker payments from BioMarin. SCJH received consulting payments and travel support from BioMarin and Homology Medicines. NL received consulting payments from Alnylam, Amicus, Astellas, BioMarin, BridgeBio, Chiesi, Genzyme/Sanofi, HemoShear, Horizon Therapeutics, Jaguar, Moderna, Nestle, PTC Therapeutics, Reneo, Shire, Synlogic, and Ultragenyx, participated as clinical trial investigator for Aeglea, Amicus, Astellas, BioMarin, Genzyme/Sanofi, Homology, Horizon, Moderna, Pfizer, Protalix, PTC Therapeutics, Reneo, Retrophin/Travere therapeutics, Shire, and Ultragenyx, as well as received speaker fees from Cycle Pharmaceuticals, Leadiant and Recordati. MCM II received consulting payments from BioMarin, Horizon Therapeutics, Rhythm Pharmaceuticals, Applied Therapeutics, Cycle Therapeutics, and Ultragenyx. ALSP received speaker fees from BioMarin. JCR received consulting payments from Applied Pharma Research, Merck Serono, BioMarin, Vitaflo, and Nutricia, speaker fees from Applied Pharma Research, Merck Serono, BioMarin Pharmaceutical, Vitaflo, Cambrooke, PIAM, LifeDiet, and Nutricia, as well as travel support from Applied Pharma Research, Merck Serono, BioMarin, Vitaflo, Cambrooke, PIAM, and Nutricia. SS received consulting payments, research grants, speaker fees, and travel support from BioMarin and participated as clinical trials investigator for BioMarin. ASV received consulting payments from BioMarin, Horizon Therapeutics, and Ultragenyx and participated as clinical trial investigator for Acadia, Alexion, BioMarin, Genzyme, Homology Medicines, Kaleido, Mallinckrodt, and Ultragenyx. JV received consulting payments from BioMarin, LogicBio Pharmaceuticals, Sangamo Therapeutics, Orphan Labs, Synlogic Therapeutics, Sanofi, Axcella Health, Agios Pharmaceuticals, and Applied Therapeutics as well as travel grants from BioMarin and LogicBio Pharmaceuticals. MW received consulting payments, speaker fees, and travel support from BioMarin, and participated as clinical trial investigator for Mallinckrodt, Roche, Wave, Cycle Therapeutics, and Intrabio. ACM participated in strategic advisory boards and received honoraria as a consultant and as a speaker for Merck Serono, BioMarin, Nestlé Health Science (SHS), Applied Pharma Research, Actelion, Retrophin, Censa, PTC Therapeutics, and Arla Food., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Vacuolar-type H+-ATPase (V-ATPase) is a multimeric complex present in a variety of cellular membranes that acts as an ATP-dependent proton pump and plays a key role in pH homeostasis and intracellular signalling pathways. In humans, 22 autosomal genes encode for a redundant set of subunits allowing the composition of diverse V-ATPase complexes with specific properties and expression. Sixteen subunits have been linked to human disease. Here we describe 26 patients harbouring 20 distinct pathogenic de novo missense ATP6V1A variants, mainly clustering within the ATP synthase α/β family-nucleotide-binding domain. At a mean age of 7 years (extremes: 6 weeks, youngest deceased patient to 22 years, oldest patient) clinical pictures included early lethal encephalopathies with rapidly progressive massive brain atrophy, severe developmental epileptic encephalopathies and static intellectual disability with epilepsy. The first clinical manifestation was early hypotonia, in 70%; 81% developed epilepsy, manifested as developmental epileptic encephalopathies in 58% of the cohort and with infantile spasms in 62%; 63% of developmental epileptic encephalopathies failed to achieve any developmental, communicative or motor skills. Less severe outcomes were observed in 23% of patients who, at a mean age of 10 years and 6 months, exhibited moderate intellectual disability, with independent walking and variable epilepsy. None of the patients developed communicative language. Microcephaly (38%) and amelogenesis imperfecta/enamel dysplasia (42%) were additional clinical features. Brain MRI demonstrated hypomyelination and generalized atrophy in 68%. Atrophy was progressive in all eight individuals undergoing repeated MRIs. Fibroblasts of two patients with developmental epileptic encephalopathies showed decreased LAMP1 expression, Lysotracker staining and increased organelle pH, consistent with lysosomal impairment and loss of V-ATPase function. Fibroblasts of two patients with milder disease, exhibited a different phenotype with increased Lysotracker staining, decreased organelle pH and no significant modification in LAMP1 expression. Quantification of substrates for lysosomal enzymes in cellular extracts from four patients revealed discrete accumulation. Transmission electron microscopy of fibroblasts of four patients with variable severity and of induced pluripotent stem cell-derived neurons from two patients with developmental epileptic encephalopathies showed electron-dense inclusions, lipid droplets, osmiophilic material and lamellated membrane structures resembling phospholipids. Quantitative assessment in induced pluripotent stem cell-derived neurons identified significantly smaller lysosomes. ATP6V1A-related encephalopathy represents a new paradigm among lysosomal disorders. It results from a dysfunctional endo-lysosomal membrane protein causing altered pH homeostasis. Its pathophysiology implies intracellular accumulation of substrates whose composition remains unclear, and a combination of developmental brain abnormalities and neurodegenerative changes established during prenatal and early postanal development, whose severity is variably determined by specific pathogenic variants., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To present a case series that illustrates real-world use of pegvaliase based on the initial experiences of US healthcare providers., Methods: Sixteen healthcare providers from 14 centers across the US with substantial clinical experience in treating patients with phenylketonuria (PKU) with pegvaliase in the two-plus years since FDA approval (May 2018) provided cases that exemplified important lessons from their initial experiences treating patients with pegvaliase. Key lessons from each case and takeaway points were discussed in both live and virtual meetings., Results: Fifteen cases of adults with PKU (eight males, seven females), representing a spectrum of age (18 to 53 years), previous PKU care, comorbidities, and socioeconomic situations were reviewed and discussed. Full extended case reports are included in the Supplement. The cases showed that treating patients with a daily injectable can be challenging due to a patient's financial problems, treatment challenges, and neuropsychological and psychiatric comorbidities, which can be identified before starting pegvaliase, but do not prohibit successful treatment. The authors agreed that patient education on adverse events (AEs), time to efficacy, dietary changes, and food preparation is an ongoing process that should start prior to initiating pegvaliase treatment. Treatment goals and planned dietary changes once efficacy is reached should be defined prior to treatment initiation and re-evaluated throughout the course of therapy. Each patient's titration schedule and dietary adjustments are unique, depending on occurrence of AEs and individual goals of treatment. Despite the AE profile of pegvaliase, all but two patients remained motivated to continue treatment and achieved efficacy (except one patient in whom titration was still ongoing). AEs occurring early in the treatment pathway may require prolongation of the titration phase and/or concomitant medication use, but do not seem indicative of future tolerability or eventual efficacy. Close follow-up of patients during titration and maintenance to help with dietary changes is important., Conclusion: This case series provides real-world experience on the use of pegvaliase. Until data from registries and independent research become available, the data presented herein can support appropriate management of patients receiving pegvaliase in clinical practice., Competing Interests: DA reports grants from BioMarin outside the submitted work. HCA and KC received payments from BioMarin to participate in the advisory board meeting related to the submitted work. HB reports personal fees from BioMarin related to the submitted work and personal fees from BioMarin, Cambrooke, Horizon, Nutricia, Ultragenyx, and Vitaflo outside the submitted work. CE received payments from BioMarin to participate in the advisory board meeting related to the submitted work, and payments from BioMarin outside the submitted work. ML received personal fees to participate in the advisory board meeting related to the submitted work; payments from BioMarin outside the submitted work; and is an investigator in clinical trials sponsored by BioMarin. JL and KW are employees of BioMarin. KL received payments from BioMarin for participating in the advisory board meeting related to the submitted work; she is currently an employee of BioMarin. MM reports personal fees and non-financial support from BioMarin related to the submitted work and personal fees from Applied Therapeutics, Cycle Pharmaceuticals and Rhythm Pharmaceuticals, personal fees and non-financial support from Aeglea Biotherapeutics and Horizon Therapeutics, and grants from Censa Pharmaceuticals outside the submitted work. JWR received payments and travel support from BioMarin for participating in the advisory board meeting related to the submitted work. HS received payments and travel support from BioMarin related to the submitted work, was involved as an investigator in clinical trials for BioMarin, and received payments from BioMarin, Vitaflo, MetEd and Symbiotics outside the submitted work. SS received consulting fees, speaker fees, and travel support from BioMarin and was involved as an investigator in clinical trials for BioMarin. DS received personal fees from BioMarin related to the submitted work and personal fees from BioMarin, Cambrooke, Horizon, Nutricia, Ultragenyx, Cycle Pharmaceuticals and Vitaflo outside the submitted work. JT-A received personal fees for participating in the advisory board related to the submitted work and personal fees from BioMarin outside the submitted work. JT was involved as an investigator in clinical trials for BioMarin and was a member of the Phase III advisory board. EV received personal fees for participating in the advisory board related to the submitted work and personal fees from BioMarin outside the submitted work. LBW received personal fees from BioMarin for participating in the advisory board and virtual platform meeting related to the submitted work, and personal fees from BioMarin and Nutricia outside the submitted work., (© 2021 The Authors.)

Background: Pegvaliase is an enzyme substitution therapy that reduces blood phenylalanine (Phe) in adults with phenylketonuria (PKU), and often allows normalization of protein intake (≥0.8 g protein/kg). Here we examine the nutrition status of adults with PKU consuming a normal protein intake without medical food after being treated with pegvaliase for ≥1 year., Methods: A cross-sectional study evaluating nutritional intake (3-day food record and food frequency questionnaire), anthropometrics, laboratory indices of protein, micronutrient, and essential fatty acid (EFA) status, and questionnaires evaluating food neophobia and Epicurean eating pleasure., Results: Participants (n = 18, 61% female) started pegvaliase 4.9 ± 2.1 years prior to enrollment and were aged 38.2 ± 8.8 years with a mean BMI of 29.2 ± 4.1 kg/m 2 . Participants consumed a mean of 73.2 ± 17.6 g protein/d (1.0 ± 0.3 g/kg/d). Eleven participants had low blood Phe (<30 μmol/L) with adequate protein intake and normal indices of protein status. Micronutrient and EFA concentrations were normal except for mildly low vitamin D (<30 ng/mL, n = 12). Intakes of sodium, saturated fat, and added sugars exceeded recommendations for healthy adults, though mean diet quality was comparable to a US adult reference population. Lower food neophobia scores correlated with an increased aesthetic appreciation of food. However, 53% of participants self-reported having moderate (n = 6) to high (n = 3) food neophobia., Discussion: Participants treated with pegvaliase consumed an unrestricted diet with adequate dietary protein and, overall, had normal protein, micronutrient, and fatty acid status. Despite low blood Phe, protein nutriture was not compromised. While nutritional deficiencies were not identified, diet quality was suboptimal and some participants reported food neophobia. Nutrition education remains an important component of care as patients adapt to a normal diet., (Copyright © 2021 Elsevier Inc. All rights reserved.)

We present Boston Children's Hospital's clinic model for pegvaliase therapy in adults with phenylketonuria (PKU) and clinical outcomes in 46 patients over the first 1.5 years of commercial therapy. Approximately 70% (18/26) of patients starting pegvaliase achieved blood phenylalanine (Phe) <360 μmol/L, with an average of a 68 ± 24% decrease in blood Phe from baseline. All patients experienced at least minor side effects, but in most, management of the side effects allowed for treatment to continue., (© 2020 The Authors.)

Purpose: Phenylketonuria (PKU) is a rare metabolic disorder that requires life-long management to reduce phenylalanine (Phe) concentrations within the recommended range. The availability of pegvaliase (PALYNZIQ™, an enzyme that can metabolize Phe) as a new therapy necessitates the provision of guidance for its use., Methods: A Steering Committee comprising 17 health-care professionals with experience in using pegvaliase through the clinical development program drafted guidance statements during a series of face-to-face meetings. A modified Delphi methodology was used to demonstrate consensus among a wider group of health-care professionals with experience in using pegvaliase., Results: Guidance statements were developed for four categories: (1) treatment goals and considerations prior to initiating therapy, (2) dosing considerations, (3) considerations for dietary management, and (4) best approaches to optimize medical management. A total of 34 guidance statements were included in the modified Delphi voting and consensus was reached on all after two rounds of voting., Conclusion: Here we describe evidence- and consensus-based recommendations for the use of pegvaliase in adults with PKU. The manuscript was evaluated against the Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument and is intended for use by health-care professionals who will prescribe pegvaliase and those who will treat patients receiving pegvaliase.

Aberrant signaling through pathways controlling cell response to extracellular stimuli constitutes a central theme in disorders affecting development. Signaling through RAS and the MAPK cascade controls a variety of cell decisions in response to cytokines, hormones, and growth factors, and its upregulation causes Noonan syndrome (NS), a developmental disorder whose major features include a distinctive facies, a wide spectrum of cardiac defects, short stature, variable cognitive impairment, and predisposition to malignancies. NS is genetically heterogeneous, and mutations in more than ten genes have been reported to underlie this disorder. Despite the large number of genes implicated, about 10%-20% of affected individuals with a clinical diagnosis of NS do not have mutations in known RASopathy-associated genes, indicating that additional unidentified genes contribute to the disease, when mutated. By using a mixed strategy of functional candidacy and exome sequencing, we identify RRAS2 as a gene implicated in NS in six unrelated subjects/families. We show that the NS-causing RRAS2 variants affect highly conserved residues localized around the nucleotide binding pocket of the GTPase and are predicted to variably affect diverse aspects of RRAS2 biochemical behavior, including nucleotide binding, GTP hydrolysis, and interaction with effectors. Additionally, all pathogenic variants increase activation of the MAPK cascade and variably impact cell morphology and cytoskeletal rearrangement. Finally, we provide a characterization of the clinical phenotype associated with RRAS2 mutations., (Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

De novo germline mutations in GNB1 have been associated with a neurodevelopmental phenotype. To date, 28 patients with variants classified as pathogenic have been reported. We add 18 patients with de novo mutations to this cohort, including a patient with mosaicism for a GNB1 mutation who presented with a milder phenotype. Consistent with previous reports, developmental delay in these patients was moderate to severe, and more than half of the patients were non-ambulatory and nonverbal. The most observed substitution affects the p.Ile80 residue encoded in exon 6, with 28% of patients carrying a variant at this residue. Dystonia and growth delay were observed more frequently in patients carrying variants in this residue, suggesting a potential genotype-phenotype correlation. In the new cohort of 18 patients, 50% of males had genitourinary anomalies and 61% of patients had gastrointestinal anomalies, suggesting a possible association of these findings with variants in GNB1. In addition, cutaneous mastocytosis, reported once before in a patient with a GNB1 variant, was observed in three additional patients, providing further evidence for an association to GNB1. We will review clinical and molecular data of these new cases and all previously reported cases to further define the phenotype and establish possible genotype-phenotype correlations., (© 2018 Wiley Periodicals, Inc.)

Germ-line interstitial deletions involving the 14q32 chromosomal region, resulting in 14q32 deletion syndrome, are rare. DICER1 is a recently described cancer-predisposition gene located at 14q32.13. We report the case of a male child with a ∼5.8 Mbp 14q32.13q32.2 germ-line deletion, which included the full DICER1 locus. We reviewed available clinical and pathological material, and conducted genetic analyses. In addition to having congenital dysmorphic features, the child developed multiple DICER1 syndrome-related tumors before age 5 y: a pediatric cystic nephroma (pCN), a ciliary body medulloepithelioma (CBME), and a small lung cyst (consistent with occult pleuropulmonary blastoma Type I/Ir cysts seen in DICER1 mutation carriers). He also developed a cerebral spindle-cell sarcoma with myogenous differentiation. Our investigations revealed that the deletion encompassed 31 protein-coding genes. In addition to the germ-line DICER1 deletion, somatic DICER1 RNase IIIb mutations were found in the CBME (c.5437G > A, p.E1813K), pCN (c.5425G > A, p.G1809R), and sarcoma (c.5125G > A, p.D1709N). The sarcoma also harbored a somatic TP53 mutation: c.844C > T, p.R282W. Additional copy number alterations were identified in the CBME and sarcoma using an OncoScan array. Among the 8 cases with molecularly-defined 14q32 deletions involving DICER1 and for whom phenotypic information is available, our patient and one other developed DICER1-related tumors. Biallelic DICER1 mutations have not previously been reported to cause cerebral sarcoma, which now may be considered a rare manifestation of the DICER1 syndrome. Our study shows that DICER1-related tumors can occur in children with 14q32 deletions and suggests surveillance for such tumors may be warranted., (© 2018 Wiley Periodicals, Inc.)

Mitochondrial DNA (mtDNA) maintenance defects are a group of diseases caused by deficiency of proteins involved in mtDNA synthesis, mitochondrial nucleotide supply, or mitochondrial dynamics. One of the mtDNA maintenance proteins is MPV17, which is a mitochondrial inner membrane protein involved in importing deoxynucleotides into the mitochondria. In 2006, pathogenic variants in MPV17 were first reported to cause infantile-onset hepatocerebral mtDNA depletion syndrome and Navajo neurohepatopathy. To date, 75 individuals with MPV17-related mtDNA maintenance defect have been reported with 39 different MPV17 pathogenic variants. In this report, we present an additional 25 affected individuals with nine novel MPV17 pathogenic variants. We summarize the clinical features of all 100 affected individuals and review the total 48 MPV17 pathogenic variants. The vast majority of affected individuals presented with an early-onset encephalohepatopathic disease characterized by hepatic and neurological manifestations, failure to thrive, lactic acidemia, and mtDNA depletion detected mainly in liver tissue. Rarely, MPV17 deficiency can cause a late-onset neuromyopathic disease characterized by myopathy and peripheral neuropathy with no or minimal liver involvement. Approximately half of the MPV17 pathogenic variants are missense. A genotype with biallelic missense variants, in particular homozygous p.R50Q, p.P98L, and p.R41Q, can carry a relatively better prognosis., (© 2017 Wiley Periodicals, Inc.)

Desmosterolosis is a rare multiple congenital anomaly syndrome caused by a defect in the enzyme 3-beta-hydroxysterol delta-24-reductase (DHCR24) in the cholesterol biosynthesis pathway. Defects in this enzyme cause increased level of the cholesterol precursor desmosterol while disrupting development of cholesterol, impacting embryogenesis. A total of 9 cases of desmosterolosis have been reported to date. We report a 20-month-old male from consanguineous parents with multiple congenital anomalies including corpus callosum hypoplasia, facial dysmorphism, cleft palate, pectus deformity, short and wide neck and distal contractures. On analysis of the regions of homozygosity found by microarray, we identified DHCR24 as a candidate gene. Sterol quantitation showed a desmosterol level of 162 μg/mL (nl: 0.82 ± 0.48). Genetic testing confirmed the diagnosis with a homozygous likely pathogenic mutation (p.Glu191Lys) in the DHCR24 gene. Our case expands the known diagnostic spectrum for Desmosterolosis. We suggest considering Desmosterolosis in the differential diagnosis of patients who present with concurrent agenesis of the corpus callosum with white matter atrophy and ventriculomegaly, retromicrognathia with or without cleft palate, hand contractures, and delay of growth and development. Children of consanguineous mattings may be at higher risk for rare recessive disorders and testing for cholesterol synthesis defect should be a consideration for affected children. Initial evaluation can be performed using sterol quantitation, followed by genetic testing., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Deletions of chromosome 1p36 affect approximately 1 in 5,000 newborns and are associated with developmental delay, intellectual disability, and defects involving the brain, eye, ear, heart, and kidney. Arginine-glutamic acid dipeptide repeats (RERE) is located in the proximal 1p36 critical region. RERE is a widely-expressed nuclear receptor coregulator that positively regulates retinoic acid signaling. Animal models suggest that RERE deficiency might contribute to many of the structural and developmental birth defects and medical problems seen in individuals with 1p36 deletion syndrome, although human evidence supporting this role has been lacking. In this report, we describe ten individuals with intellectual disability, developmental delay, and/or autism spectrum disorder who carry rare and putatively damaging changes in RERE. In all cases in which both parental DNA samples were available, these changes were found to be de novo. Associated features that were recurrently seen in these individuals included hypotonia, seizures, behavioral problems, structural CNS anomalies, ophthalmologic anomalies, congenital heart defects, and genitourinary abnormalities. The spectrum of defects documented in these individuals is similar to that of a cohort of 31 individuals with isolated 1p36 deletions that include RERE and are recapitulated in RERE-deficient zebrafish and mice. Taken together, our findings suggest that mutations in RERE cause a genetic syndrome and that haploinsufficiency of RERE might be sufficient to cause many of the phenotypes associated with proximal 1p36 deletions., (Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: Genomic microarrays have been used as the first-tier cytogenetic diagnostic test for patients with developmental delay/intellectual disability, autism spectrum disorders and/or multiple congenital anomalies. The use of SNP arrays has revealed regions of homozygosity in the genome which can lead to identification of uniparental disomy and parental consanguinity in addition to copy number variations. Consanguinity is associated with an increased risk of birth defects and autosomal recessive disorders. However, the frequency of parental consanguinity in children with developmental disabilities is unknown, and consanguineous couples may not be identified during doctor's visit or genetic counseling without microarray., Results: We studied 607 proband pediatric patients referred for developmental disorders using a 4 × 180 K array containing both CGH and SNP probes. Using 720, 360, 180, and 90 Mb as the expected sizes of homozygosity for an estimated coefficient of inbreeding (F) 1/4, 1/8, 1/16, 1/32, parental consanguinity was detected in 21cases (3.46%)., Conclusion: Parental consanguinity is not uncommon in children with developmental problems in our study population, and can be identified by use of a combined CGH and SNP chromosome microarray. Identification of parental consanguinity in such cases can be important for further diagnostic testing.

We present three patients with overlapping interstitial deletions of 19p13.3 identified by high resolution SNP microarray analysis. All three had a similar phenotype characterized by intellectual disability or developmental delay, structural heart abnormalities, large head relative to height and weight or macrocephaly, and minor facial anomalies. Deletion sizes ranged from 792 Kb to 1.0 Mb and included a common region arr [hg19] 19p13.3 (3,814,392-4,136,989), containing eight genes: ZFR2, ATCAY, NMRK2, DAPK3, EEF2, PIAS4, ZBTB7A, MAP2K2, and two non-coding RNA's MIR637 and SNORDU37. The patient phenotypes were compared with three previous single patient reports with similar interstitial 19p13.3 deletions and six additional patients from the DECIPHER and ISCA databases to determine if a common haploinsufficient phenotype for the region can be established., (Copyright © 2013 Wiley Periodicals, Inc.)

Individuals with isolated terminal deletions of 8p have been well described in the literature, however, molecular characterization, particularly by microarray, of the deletion in most instances is lacking. The phenotype of such individuals falls primarily into two categories: those with cardiac defects, and those without. The architecture of 8p has been demonstrated to contain two inversely oriented segmental duplications at 8p23.1, flanking the gene, GATA4. Haploinsufficiency of this gene has been implicated in cardiac defects seen in numerous individuals with terminal 8p deletion. Current microarray technologies allow for the precise elucidation of the size and gene content of the deleted region. We present three individuals with isolated terminal deletion of 8p distal to the segmental duplication telomeric to GATA4. These individuals present with a relatively mild and nonspecific phenotype including mildly dysmorphic features, developmental delay, speech delay, and early behavior issues., (Copyright © 2013 Wiley Periodicals, Inc.)

Haploinsufficiency of ANKRD11 encoding ankyrin repeat domain-containing protein 11 was recently reported as the cause of a syndrome due to microdeletion, characterized by intellectual disability with minor facial anomalies and short stature. Most recently, intragenic mutations of ANKRD11 were found in a cohort of patients with KBG syndrome. KBG is an autosomal dominant intellectual disability syndrome characterized by short stature, characteristic facial appearance, macrodontia, and skeletal anomalies. It remains unknown if deletion of the entire ANKRD11 causes KBG syndrome. We present a mother and child with a heterozygous 365 Kb deletion at 16q24.3 containing ANKRD11, ZNF778, and SPG7 genes. The child presented with developmental delay, facial anomalies, hand anomalies, and a congenital heart defect. The mother has short stature, facial anomalies, macrodontia, hand anomalies, and learning disability. Both individuals had many findings reported in KBG syndrome and the family met the suggested diagnostic criteria. However, typical macrodontia with fused incisors, costovertebral anomalies, and delayed bone age were not present. We conclude that microdeletions involving ANKRD11 result in a phenotype similar to that of KBG syndrome. © 2012 Wiley Periodicals, Inc., (Copyright © 2012 Wiley Periodicals, Inc.)

Copy number variations (CNVs) play a crucial role in the intricate genetics of autism spectrum disorders. A region on chromosome 15q24 vulnerable to both deletions and duplications has been previously implicated in a range of phenotypes including autism, Asperger's syndrome, delayed development, and mild to severe mental retardation. Prior studies have delineated a minimal critical region of approximately 1.33 Mb. In this study, a multiplex autism family was evaluated for CNVs using genotyping data from the Illumina 1 M BeadChip and analyzed with the PennCNV algorithm. Variants were then identified that co-segregate with autism features in this family. Here, we report autistic first cousins who carry two microduplications concordant with disease. Both duplications were inherited maternally and found to be identical by descent. The first is an approximately 10,000 base pair microduplication within the minimal region on 15q24 that falls across a single gene, ubiquitin-like 7. This is the smallest duplication in the region to result in a neuropsychiatric disorder, potentially narrowing the critical region for susceptibility to developmental and autism spectrum disorders. The second is a novel, 352 kb tandem duplication on 7p21 that replicates part of the neurexophilin 1 and islet cell autoantigen 1 genes. The breakpoint junction falls within the intronic regions of these genes and demonstrates a microhomology of four base pairs. Each of these microduplications may contribute to the complex etiology of autism spectrum disorders., (Copyright © 2011 Wiley-Liss, Inc.)

Copy number variations (CNVs) are a major cause of genetic disruption in the human genome with far more nucleotides being altered by duplications and deletions than by single nucleotide polymorphisms (SNPs). In the multifaceted etiology of autism spectrum disorders (ASDs), CNVs appear to contribute significantly to our understanding of the pathogenesis of this complex disease. A unique resource of 42 extended ASD families was genotyped for over 1 million SNPs to detect CNVs that may contribute to ASD susceptibility. Each family has at least one avuncular or cousin pair with ASD. Families were then evaluated for co-segregation of CNVs in ASD patients. We identified a total of five deletions and seven duplications in eleven families that co-segregated with ASD. Two of the CNVs overlap with regions on 7p21.3 and 15q24.1 that have been previously reported in ASD individuals and two additional CNVs on 3p26.3 and 12q24.32 occur near regions associated with schizophrenia. These findings provide further evidence for the involvement of ICA1 and NXPH1 on 7p21.3 in ASD susceptibility and highlight novel ASD candidates, including CHL1, FGFBP3 and POUF41. These studies highlight the power of using extended families for gene discovery in traits with a complex etiology.

Purpose: The implementation of the expanded newborn screening panel of 29 disorders recommended by the American College of Medical Genetics in Puerto Rico and United States Virgin Islands is still in development or in early stages. Efforts in the territories are complicated by educational and resource barriers that generate a wide gap between the islands and the US mainland., Methods: To meet immediate educational needs, we conducted in-services for local newborn screening professionals. The efficacy of the educational intervention was measured by pre and posttest scores and a seminar evaluation. An assessment was obtained to document local newborn screening needs and barriers, with focus on human resources, intervention, language, social issues, education, and communication., Results: Statistical significance was found (P value < or =0.05) between pre and posttest scores of the educational intervention. Needs and barriers associated with expanded newborn screening were also documented., Conclusion: Puerto Rico and United States Virgin Islands face different challenges in their implementation of expanded newborn screening. The data obtained in the present study serves as foundation for the development of public policy and long-term educational programs.

Genomic imbalance is a major cause of developmental disorders. Microarray-based comparative genomic hybridization (aCGH) has revealed frequent imbalances associated with clinical syndromes, but also a large number of copy number variations (CNVs), which have complicated the interpretation of results. We studied 100 consecutive patients with unexplained mental retardation and a normal karyotype using several platforms of CGH arrays. A genomewide array with 44,290 oligonucleotide probes (OaCGH44K) detected imbalances in 15% of cases studied with sizes ranged from 459 kb to 19 Mb while revealing a small number of CNVs (0.72/individual). Another platform with approximately 240,000 oligonucleotide probes (OaCGH244K) revealed a large number of CNVs (20/individual) in selected cases and their normal parents. We used a comprehensive approach for interpreting the results of aCGH, including consideration of the size, inheritance and gene content of CNVs, and consultation with an online Database of Genomic Variants (DGV) and Online Mendelian Inheritance in Men (OMIM) for information on the genes involved. Our study suggests that genomewide oligonucleotide arrays such as the OaCGH44K platform can be used as a powerful diagnostic tool for detection of genomic imbalances associated with unexplained mental retardation or syndromic autism spectrum disorders. It is interesting to note that a small number of common variants were revealed by OaCGH244K in some study subjects but not in their parents and that some inherited CNVs had altered breakpoints. Further investigations on these alterations may provide useful information for understanding the mechanism of CNVs., (2007 Wiley-Liss, Inc.)