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Objective: De novo variants in cullin-3 ubiquitin ligase (CUL3) have been strongly associated with neurodevelopmental disorders (NDDs), but no large case series have been reported so far. Here, we aimed to collect sporadic cases carrying rare variants in CUL3, describe the genotype-phenotype correlation, and investigate the underlying pathogenic mechanism., Methods: Genetic data and detailed clinical records were collected via multicenter collaboration. Dysmorphic facial features were analyzed using GestaltMatcher. Variant effects on CUL3 protein stability were assessed using patient-derived T-cells., Results: We assembled a cohort of 37 individuals with heterozygous CUL3 variants presenting a syndromic NDD characterized by intellectual disability with or without autistic features. Of these, 35 have loss-of-function (LoF) and 2 have missense variants. CUL3 LoF variants in patients may affect protein stability leading to perturbations in protein homeostasis, as evidenced by decreased ubiquitin-protein conjugates in vitro. Notably, we show that 4E-BP1 (EIF4EBP1), a prominent substrate of CUL3, fails to be targeted for proteasomal degradation in patient-derived cells., Interpretation: Our study further refines the clinical and mutational spectrum of CUL3-associated NDDs, expands the spectrum of cullin RING E3 ligase-associated neuropsychiatric disorders, and suggests haploinsufficiency via LoF variants is the predominant pathogenic mechanism. ANN NEUROL 2024., (© 2024 American Neurological Association.)

We describe the clinical presentation and evaluation of a 10-year-old boy who presented to our medical center with years of progressive proximal muscle weakness, muscle atrophy, and weight loss. In addition to a myopathic phenotype, he was found to have tachycardia, tremor, and learning difficulties. Electromyography revealed chronic myopathic changes and laboratory screening was notable for undetectable thyroid stimulating hormone. Follow-up testing revealed elevated thyroid peroxidase antibodies and thyroid stimulating immunoglobulins. Ultrasound examination revealed an enlarged heterogeneous thyroid gland. Four weeks after treatment with atenolol and methimazole, his strength and cognition began to improve. This case highlights the importance of evaluating for potentially reversible toxic-metabolic etiologies in children presenting with any progressive neurologic symptoms., (Copyright © 2024 by the American Academy of Pediatrics.)

Supravalvar aortic stenosis (SVAS) is a less common but clinically important form of left ventricular outflow tract obstruction, and commonly associated with Williams syndrome (WS). SVAS outside of WS may also occur sporadically or in a familial form, often with identifiable mutations in the elastin (ELN) gene. While risk of sudden cardiac death in patients with SVAS has been extensively described in the context of WS, less is known about risk in patients with isolated SVAS. We report a case of a nonsyndromic two-year-old boy with evolving manifestations of SVAS who developed sudden cardiac arrest and death during a sedated cardiac magnetic resonance imaging study. A strong family history of SVAS was present and targeted genetic testing identified an ELN gene mutation in the boy's affected father and other paternal relatives. We review risk factors found in the literature for SCA in SVAS patients and utilize this case to raise awareness of the risk of cardiac events in these individuals even in the absence of WS or severe disease. This case also underscores the importance of genetic testing, including targeted panels specifically looking for ELN gene mutations, in all patients with SVAS even in the absence of phenotypic concerns for WS or other genetic syndromes., (© 2023. The Author(s).)

The short pre-M1 helix within the S1-M1 linker (also referred to as the pre-M1 linker) between the agonist-binding domain (ABD, S1) and the M1 transmembrane helix of the NMDA receptor (NMDAR) is devoid of missense variants within the healthy population but is a locus for de novo pathogenic variants associated with neurological disorders. Several de novo variants within this helix have been identified in patients presenting early in life with intellectual disability, developmental delay, and/or epilepsy. In this study, we evaluated functional properties for twenty variants within the pre-M1 linker in GRIN1, GRIN2A, and GRIN2B genes, including six novel missense variants. The effects of pre-M1 variants on agonist potency, sensitivity to endogenous allosteric modulators, response time course, channel open probability, and surface expression were assessed. Our data indicated that virtually all of the variants evaluated altered channel function, and multiple variants had profound functional consequences, which may contribute to the neurological conditions in the patients harboring the variants in this region. These data strongly suggest that the residues within the pre-M1 helix play a key role in channel gating and are highly intolerant to genetic variation., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: The objectives of this study were to define the clinical and biochemical spectrum of spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) and to determine if aberrant cellular ceramide accumulation could be normalized by enzyme replacement., Methods: Clinical features of 6 patients with SMA-PME were assessed by retrospective chart review, and a literature review of 24 previously published cases was performed. Leukocyte enzyme activity of acid ceramidase was assessed with a fluorescence-based assay. Skin fibroblast ceramide content and was assessed by high performance liquid chromatography, electrospray ionization tandem mass spectroscopy. Enzyme replacement was assessed using recombinant human acid ceramidase (rhAC) in vitro., Results: The six new patients showed the hallmark features of SMA-PME, with variable initial symptom and age of onset. Five of six patients carried at least one of the recurrent SMA-PME variants observed in two specific codons of ASAH1. A review of 30 total cases revealed that patients who were homozygous for the most common c.125C > T variant presented in the first decade of life with limb-girdle weakness as the initial symptom. Sensorineural hearing loss was associated with the c.456A > C variant. Leukocyte acid ceramidase activity varied from 4.1%-13.1% of controls. Ceramide species in fibroblasts were detected and total cellular ceramide content was elevated by 2 to 9-fold compared to controls. Treatment with rhAC normalized ceramide profiles in cultured fibroblasts to control levels within 48 h., Interpretation: This study details the genotype-phenotype correlations observed in SMA-PME and shows the impact of rhAC to correct the abnormal cellular ceramide profile in cells., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Au-Kline syndrome (AKS) is a neurodevelopmental disorder associated with multiple malformations and a characteristic facial gestalt. The first individuals ascertained carried de novo loss-of-function (LoF) variants in HNRNPK. Here, we report 32 individuals with AKS (26 previously unpublished), including 13 with de novo missense variants. We propose new clinical diagnostic criteria for AKS that differentiate it from the clinically overlapping Kabuki syndrome and describe a significant phenotypic expansion to include individuals with missense variants who present with subtle facial features and few or no malformations. Many gene-specific DNA methylation (DNAm) signatures have been identified for neurodevelopmental syndromes. Because HNRNPK has roles in chromatin and epigenetic regulation, we hypothesized that pathogenic variants in HNRNPK may be associated with a specific DNAm signature. Here, we report a unique DNAm signature for AKS due to LoF HNRNPK variants, distinct from controls and Kabuki syndrome. This DNAm signature is also identified in some individuals with de novo HNRNPK missense variants, confirming their pathogenicity and the phenotypic expansion of AKS to include more subtle phenotypes. Furthermore, we report that some individuals with missense variants have an "intermediate" DNAm signature that parallels their milder clinical presentation, suggesting the presence of an epi-genotype phenotype correlation. In summary, the AKS DNAm signature may help elucidate the underlying pathophysiology of AKS. This DNAm signature also effectively supported clinical syndrome delineation and is a valuable aid for variant interpretation in individuals where a clinical diagnosis of AKS is unclear, particularly for mild presentations., Competing Interests: Declaration of interests H.T.B. is a consultant for Mahzi therapeutics., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Prader-Willi syndrome (PWS) is an imprinting disorder caused by the absence of paternal expressed genes in the Prader-Willi critical region (PWCR) on chromosome 15q11.2-q13. Three molecular mechanisms have been known to cause PWS, including a deletion in the PWCR, uniparental disomy 15 and imprinting defects., Results: We report the first case of PWS associated with a single-nucleotide SNRPN variant in a 10-year-old girl presenting with clinical features consistent with PWS, including infantile hypotonia and feeding difficulty, developmental delay with cognitive impairment, excessive eating with central obesity, sleep disturbances, skin picking and related behaviour issues. Whole-exome sequencing revealed a de novo mosaic nonsense variant of the SNRPN gene (c.73C>T, p.R25X) in 10% of DNA isolated from buccal cells and 19% of DNA from patient-derived lymphoblast cells. DNA methylation study did not detect an abnormal methylation pattern in the SNRPN locus. Parental origin studies showed a paternal source of an intronic single-nucleotide polymorphism within the locus in proximity to the SNRPN variant., Conclusions: This is the first report that provides evidence of a de novo point mutation of paternal origin in SNRPN as a new disease-causing mechanism for PWS. This finding suggests that gene sequencing should be considered as part of the diagnostic workup in patients with clinical suspicion of PWS., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Our previous work demonstrating enrichment of outflow tract (OFT) congenital heart disease (CHD) in children with cleft lip and/or palate (CL/P) suggests derangements in common underlying developmental pathways. The current pilot study examines the underlying genetics of concomitant nonsyndromic CL/P and OFT CHD phenotype. Of 575 patients who underwent CL/P surgery at Children's Hospital Los Angeles, seven with OFT CHD, negative chromosomal microarray analysis, and no recognizable syndromic association were recruited with their parents (as available). Whole genome sequencing of blood samples paired with whole-blood-based RNA sequencing for probands was performed. A pathogenic or potentially pathogenic variant was identified in 6/7 (85.7%) probands. A total of seven candidate genes were mutated (CHD7, SMARCA4, MED12, APOB, RNF213, SETX, and JAG1). Gene ontology analysis of variants predicted involvement in binding (100%), regulation of transcription (42.9%), and helicase activity (42.9%). Four patients (57.1%) expressed gene variants (CHD7, SMARCA4, MED12, and RNF213) previously involved in the Wnt signaling pathway. Our pilot analysis of a small cohort of patients with combined CL/P and OFT CHD phenotype suggests a potentially significant prevalence of deleterious mutations. In our cohort, an overrepresentation of mutations in molecules associated with Wnt-signaling was found. These variants may represent an expanded phenotypic heterogeneity within known monogenic disease genes or provide novel evidence of shared developmental pathways. The mechanistic implications of these mutations and subsequent developmental derangements resulting in the CL/P and OFT CHD phenotype require further analysis in a larger cohort of patients., (© 2022 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Background: The majority of research to understand the risk factors of nonsyndromic orofacial clefts (NSOFCs) has been conducted in high-income populations. Although patients with NSOFCs in low- and middle-income countries (LMICs) are at the highest risk of not receiving care, global health infrastructure allows innovative partnerships to explore the etiologic mechanisms of cleft and targets for prevention unique to these populations., Methods: The International Family Study (IFS) is an ongoing case-control study with supplemental parental trio data designed to examine genetic, environmental, lifestyle, and sociodemographic risk factors for NSOFCs in 8 LMICs (through August 2020). Interview and biological samples are collected for each family. The interview includes demographics, family history of cleft, diet and water sources, maternal pregnancy history, and other lifestyle and environmental factors., Results: Seven of 8 countries are currently summarized (2012-2017) for a total of 2955 case and 2774 control families with 11 946 unique biological samples from Vietnam, Philippines, Honduras, Madagascar, Morocco, Democratic Republic of the Congo, and Nicaragua. The phenotype distribution was 1641 (55.5%) cases with cleft lip and palate, 782 (26.5%) with cleft lip (CL), and 432 (14.6%) with cleft palate (CP)., Discussion: The International Family Study is the largest case set of NSOFCs with an associated biobank in LMICs currently assembled. The biobank, family, and case-control study now include samples from 8 LMICs where local health care infrastructure cannot address the surgical burden of cleft or investigate causal mechanisms. The International Family Study can be a source of information and may collaborate with local public health institutions regarding education and interventions to potentially prevent NSOFCs.

Research has shown that genetics play a key role in the development of autism spectrum disorder (ASD). ASD has been linked to many genes and is a prominent feature in numerous genetic disorders. A genetic evaluation should be offered to any patient who receives a diagnosis of ASD, including deep phenotyping and genetic testing when clinically indicated. When insurance does not cover genetic testing for ASD patients, the lack of medical utility is often cited as a reason for prior authorization request denial. However, ample evidence exists that genetic testing has the power to change clinical management in many of these patients. Genetic testing that results in a diagnosis guides clinicians to screen for associated medical conditions and can direct targeted medical interventions. Given the potential for clinically actionable results, it is important that genetic testing be available and accessible to all patients with ASD.