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ObjectiveTo characterise the obstetrical management and outcomes in a series of women with a history of Kawasaki disease (KD) in childhood.DesignRetrospective case series.SettingTertiary healthcare setting in the USA.PopulationWomen with a history of KD in childhood.MethodsWomen completed a detailed health questionnaire and participated in research imaging studies as part of the San Diego Adult KD Collaborative Study.Main outcome measuresObstetrical management, complications during pregnancy and delivery, and infant outcomes.ResultsTen women with a history of KD in childhood carried a total of 21 pregnancies to term. There were no cardiovascular complications during labour and delivery despite important cardiovascular abnormalities in four of the ten subjects. Pregnancy was complicated by pre-eclampsia and the post-partum course was complicated by haemorrhage in one subject each. Two of the 21 progeny subsequently developed KD.ConclusionsWomen with important cardiovascular sequelae from KD in childhood should be managed by a team that includes both a maternal-fetal medicine specialist and a cardiologist. Pre-pregnancy counselling should include delineation of the woman's current functional and structural cardiovascular status and appropriate adjustment of medications, but excellent outcomes are possible with appropriate care. Review of the English and Japanese literature on KD and pregnancy revealed the occurrence of myocardial infarction during pregnancy in women with missed KD and aneurysms that were not diagnosed until their acute event. Our study highlights the need for counselling with regard to the increased genetic risk of KD in offspring born to these mothers.

Aliphatic polyesters have received considerable attention in recent years due to their biodegradability and biocompatible, mechanical, and thermal properties that can make them a suitable alternative to today's commercialized polymers. The ring-opening copolymerization (ROCOP) of epoxides and cyclic anhydrides is a route to synthesize a diverse array of polyesters that could be useful in many applications. However, the catalysts used rarely consider biocompatible catalysts in the case that any are left in the polymer. To the best of our knowledge, we report the first example of using deep eutectic solvents (DESs) as biocompatible catalysts for this target ROCOP with polymerization activity for at least six diverse monomer pairs. Choline halide salts are active for this polymerization, with dried salts showing polymerization slower than that of those conducted in air. Hydrogen bonding with water is hypothesized to enhance the rate-determining step of epoxide ring opening. While the presence of water improves the rate of polymerization, it also acts as a chain transfer agent, leading to smaller molar mass polymers than intended. Combining the choline halide salts with urea or ethylene glycol hydrogen bond donors in air led to DES catalysts that reacted similarly to the salts exposed to air. However, when generating these DESs in air-free conditions, they showed similar rates of polymerization without a drop in polymer molar mass. The hydrogen bonding provided by urea and ethylene glycol seems to promote the rate increase without serving as a chain transfer agent. Results reported herein display the promising potential of biocompatible catalyst systems for this ROCOP process as well as introducing the use of hydrogen bonding to enhance polymerization rates., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Perfluoroalkyl substances (PFAS), known as "forever chemicals," are a growing concern in the sphere of human and environmental health. In response, rapid, reproducible, and inexpensive methods for PFAS detection in the environment and home water supplies are needed. We have developed a simple and inexpensive perfluoroalkyl acid detection method based on an electrically read lateral flow assay (e-LFA). Our method employs a fluorous surfactant formulation with undoped polyaniline (F-PANI) fabricated to create test lines for the lateral flow assay. In perfluoroalkyl acid sensing studies, an increase in conductivity of the F-PANI film is caused by acidification and doping of PANI. A conductivity enhancement by 10 4 -fold can be produced by this method, and we demonstrate a limit of detection for perfluorooctanoic acid (PFOA) of 400 ppt and perfluorobutanoic acid of 200 ppt. This method for PFOA detection can be expanded for wide-scale environmental and at-home water testing., Competing Interests: Competing interests statement:A general patent was filed that anticipated this invention. We plan to file a continuation in part application that details this invention in the next year. T.M.S. is the only coauthor on the first patent.

THOC6 variants are the genetic basis of autosomal recessive THOC6 Intellectual Disability Syndrome (TIDS). THOC6 is critical for mammalian Transcription Export complex (TREX) tetramer formation, which is composed of four six-subunit THO monomers. The TREX tetramer facilitates mammalian RNA processing, in addition to the nuclear mRNA export functions of the TREX dimer conserved through yeast. Human and mouse TIDS model systems revealed novel THOC6-dependent, species-specific TREX tetramer functions. Germline biallelic Thoc6 loss-of-function (LOF) variants result in mouse embryonic lethality. Biallelic THOC6 LOF variants reduce the binding affinity of ALYREF to THOC5 without affecting the protein expression of TREX members, implicating impaired TREX tetramer formation. Defects in RNA nuclear export functions were not detected in biallelic THOC6 LOF human neural cells. Instead, mis-splicing was detected in human and mouse neural tissue, revealing novel THOC6-mediated TREX coordination of mRNA processing. We demonstrate that THOC6 is required for key signaling pathways known to regulate the transition from proliferative to neurogenic divisions during human corticogenesis. Together, these findings implicate altered RNA processing in the developmental biology of TIDS neuropathology., (© 2024. The Author(s).)

Over two dozen spliceosome proteins are involved in human diseases, also referred to as spliceosomopathies. WW domain-binding protein 4 (WBP4) is part of the early spliceosomal complex and has not been previously associated with human pathologies in the Online Mendelian Inheritance in Man (OMIM) database. Through GeneMatcher, we identified ten individuals from eight families with a severe neurodevelopmental syndrome featuring variable manifestations. Clinical manifestations included hypotonia, global developmental delay, severe intellectual disability, brain abnormalities, musculoskeletal, and gastrointestinal abnormalities. Genetic analysis revealed five different homozygous loss-of-function variants in WBP4. Immunoblotting on fibroblasts from two affected individuals with different genetic variants demonstrated a complete loss of protein, and RNA sequencing analysis uncovered shared abnormal splicing patterns, including in genes associated with abnormalities of the nervous system, potentially underlying the phenotypes of the probands. We conclude that bi-allelic variants in WBP4 cause a developmental disorder with variable presentations, adding to the growing list of human spliceosomopathies., Competing Interests: Declaration of interests H.M.-S. is an employee of Geneyx Genomics., (Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

We examine the outcomes associated with childhood adversity for women with and without carefully diagnosed childhood ADHD, via an ethnically diverse sample of 140 participants with ADHD (M age  = 9.7) and 88 age- and ethnicity-matched comparisons (M age  = 9.4). At adult follow-up, we retained 211 of the original 228 participants (92.6%; M age  = 25.6). We used latent class analysis to identify patterns of childhood adversity and examine their association with adult global functioning and psychopathology. Key findings: (1) Four childhood adversity classes emerged (Low Exposure, Familial Dysfunction, Emotional Maltreatment, Pervasive Exposure); (2) Childhood ADHD predicted membership in the Emotional Maltreatment class; and (3) Childhood adversity classes were differently associated with adult outcomes, such that membership in both the Emotional Maltreatment and Pervasive Exposure classes predicted significantly higher internalizing and externalizing symptoms as well as significantly lower global functioning than women in the Low Exposure class. Furthermore, compared to the Emotional Maltreatment class, the Familial Dysfunction class had lower externalizing symptoms, whereas the Pervasive Exposure class had lower global functioning and higher internalizing symptoms by adulthood. Findings provide information about girls and women who could be targeted for intervention in terms of ADHD behavior patterns plus adverse experiences in childhood. Beyond limitations, we discuss the need to investigate the confluence of neurodevelopmental conditions and adverse child events with respect to maladaptive outcomes., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Syngnathia is an ultrarare craniofacial malformation characterised by an inability to open the mouth due to congenital fusion of the upper and lower jaws. The genetic causes of isolated bony syngnathia are unknown., Methods: We used whole exome and Sanger sequencing and microsatellite analysis in six patients (from four families) presenting with syngnathia. We used CRISPR/Cas9 genome editing to generate vgll2a and vgll4l germline mutant zebrafish, and performed craniofacial cartilage analysis in homozygous mutants., Results: We identified homozygous truncating variants in vestigial-like family member 2 ( VGLL2 ) in all six patients. Two alleles were identified: one in families of Turkish origin and the other in families of Moroccan origin, suggesting a founder effect for each. A shared haplotype was confirmed for the Turkish patients. The VGLL family of genes encode cofactors of TEAD transcriptional regulators. Vgll2 is regionally expressed in the pharyngeal arches of model vertebrate embryos, and morpholino-based knockdown of vgll2a in zebrafish has been reported to cause defects in development of pharyngeal arch cartilages. However, we did not observe craniofacial anomalies in vgll2a or vgll4l homozygous mutant zebrafish nor in fish with double knockout of vgll2a and vgll4l . In Vgll2 -/- mice, which are known to present a skeletal muscle phenotype, we did not identify defects of the craniofacial skeleton., Conclusion: Our results suggest that although loss of VGLL2 leads to a striking jaw phenotype in humans, other vertebrates may have the capacity to compensate for its absence during craniofacial development., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Nuclear receptor subfamily 2 group F member 2 (NR2F2 or COUP-TF2) encodes a transcription factor which is expressed at high levels during mammalian development. Rare heterozygous Mendelian variants in NR2F2 were initially identified in individuals with congenital heart disease (CHD), then subsequently in cohorts of congenital diaphragmatic hernia (CDH) and 46,XX ovotesticular disorders/differences of sexual development (DSD); however, the phenotypic spectrum associated with pathogenic variants in NR2F2 remains poorly characterized. Currently, less than 40 individuals with heterozygous pathogenic variants in NR2F2 have been reported. Here, we review the clinical and molecular details of 17 previously unreported individuals with rare heterozygous NR2F2 variants, the majority of which were de novo. Clinical features were variable, including intrauterine growth restriction (IUGR), CHD, CDH, genital anomalies, DSD, developmental delays, hypotonia, feeding difficulties, failure to thrive, congenital and acquired microcephaly, dysmorphic facial features, renal failure, hearing loss, strabismus, asplenia, and vascular malformations, thus expanding the phenotypic spectrum associated with NR2F2 variants. The variants seen were predicted loss of function, including a nonsense variant inherited from a mildly affected mosaic mother, missense and a large deletion including the NR2F2 gene. Our study presents evidence for rare, heterozygous NR2F2 variants causing a highly variable syndrome of congenital anomalies, commonly associated with heart defects, developmental delays/intellectual disability, dysmorphic features, feeding difficulties, hypotonia, and genital anomalies. Based on the new and previous cases, we provide clinical recommendations for evaluating individuals diagnosed with an NR2F2-associated disorder., (© 2023. The Author(s), under exclusive licence to European Society of Human Genetics.)

Objective: We explore patterns of childhood adversity (CA) in youth entering residential care. We also examine possible sex differences as well as the association between these patterns and key indicators of clinical functioning, including emotional problems, conduct problems, hyperactivity/inattention, prosocial behavior, peer problems, and trauma symptoms., Method: Data were obtained from archival records of 2,066 youth ( M age = 15.57, SD = 1.57) entering a family style residential program for the first time. The sample composition was: 65% boys, 45.8% White, 26.0% Black or African American, 12.5% Hispanic or Latino, 10.5% Multiracial, and 5.1% Other race. Inclusive latent class analysis was used to identify profiles of CA. Profile membership was used to examine sex differences and predict clinical functioning., Results: Five CA profiles were found: (1) Low Exposure, (2) Familial Dysfunction, (3) Neglect/Emotional Abuse, (4) High Exposure without Sexual Abuse, and (5) High Exposure with Sexual Abuse. Girls were more likely than boys to be in Neglect/Emotional Abuse and High Exposure with Sexual Abuse profiles. Each CA profile was associated with distinct clinical outcomes., Conclusions: This study highlights the importance of considering CA patterns when working with youth entering residential care. CA screening and classification during residential care admissions could better inform interventions for youth and their families and potentially improve the effectiveness of mental health services received. Future research should continue to study the connections between CA profiles and clinical outcomes. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Mutations of G protein-coupled receptors (GPCRs) cause various human diseases, but the mechanistic details are limited. Here, we establish p.E303K in the gene encoding the endothelin receptor type A (ETAR/EDNRA) as a recurrent mutation causing mandibulofacial dysostosis with alopecia (MFDA), with craniofacial changes similar to those caused by p.Y129F. Mouse models carrying either of these missense mutations exhibited a partial maxillary-to-mandibular transformation, which was rescued by deleting the ligand endothelin 3 (ET3/EDN3). Pharmacological experiments confirmed the causative ETAR mutations as gain of function, dependent on ET3. To elucidate how an amino acid substitution far from the ligand binding site can increase ligand affinity, we used molecular dynamics (MD) simulations. E303 is located at the intracellular end of transmembrane domain 6, and its replacement by a lysine increased flexibility of this portion of the helix, thus favoring G protein binding and leading to G protein-mediated enhancement of agonist affinity. The Y129F mutation located under the ligand binding pocket reduced the sodium-water network, thereby affecting the extracellular portion of helices in favor of ET3 binding. These findings provide insight into the pathogenesis of MFDA and into allosteric mechanisms regulating GPCR function, which may provide the basis for drug design targeting GPCRs.

Purpose: KLHL20 is part of a CUL3-RING E3 ubiquitin ligase involved in protein ubiquitination. KLHL20 functions as the substrate adaptor that recognizes substrates and mediates the transfer of ubiquitin to the substrates. Although KLHL20 regulates neurite outgrowth and synaptic development in animal models, a role in human neurodevelopment has not yet been described. We report on a neurodevelopmental disorder caused by de novo missense variants in KLHL20., Methods: Patients were ascertained by the investigators through Matchmaker Exchange. Phenotyping of patients with de novo missense variants in KLHL20 was performed., Results: We studied 14 patients with de novo missense variants in KLHL20, delineating a genetic syndrome with patients having mild to severe intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, hyperactivity, and subtle dysmorphic facial features. We observed a recurrent de novo missense variant in 11 patients (NM_014458.4:c.1069G>A p.[Gly357Arg]). The recurrent missense and the 3 other missense variants all clustered in the Kelch-type β-propeller domain of the KLHL20 protein, which shapes the substrate binding surface., Conclusion: Our findings implicate KLHL20 in a neurodevelopmental disorder characterized by intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, and hyperactivity., Competing Interests: Conflict of Interest M.M.M. and R.E.S. are employees of GeneDx, Inc. All other authors declare no conflict interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Auriculocondylar syndrome (ACS) is a rare craniofacial disorder characterized by mandibular hypoplasia and an auricular defect at the junction between the lobe and helix, known as a "Question Mark Ear" (QME). Several additional features, originating from the first and second branchial arches and other tissues, have also been reported. ACS is genetically heterogeneous with autosomal dominant and recessive modes of inheritance. The mutations identified to date are presumed to dysregulate the endothelin 1 signaling pathway. Here we describe 14 novel cases and reassess 25 published cases of ACS through a questionnaire for systematic data collection. All patients harbor mutation(s) in PLCB4, GNAI3, or EDN1. This series of patients contributes to the characterization of additional features occasionally associated with ACS such as respiratory, costal, neurodevelopmental, and genital anomalies, and provides management and monitoring recommendations., (© 2022 Wiley Periodicals LLC.)

Cleft palate lateral synechia (CPLS) syndrome is an extremely rare congenital malformation syndrome of unknown origin, characterized by the association of cleft palate and one or more intraoral lateral synechiae (OMIM # 119550). Fewer than 20 cases have been described to date. The clinical and histological findings and results of genetic investigations for two additional cases of CPLS are presented herein, in order to better delineate this syndrome, within the context of the relevant literature. The first case presented with a U-shaped cleft palate, bilateral synechiae, and Pierre Robin sequence, requiring early sectioning of the synechiae because of severe feeding problems. The second case presented with a V-shaped cleft palate and a single synechia, running from the left border of the cleft to the floor of the mouth, and was without feeding difficulties. In both cases, histopathological examination of the synechiae revealed an aspect of mucous membranes macroscopically, while staining of sections indicated lymphocyte infiltrates and parakeratosis with stratified squamous epithelium, associated with vessel and connective tissue abnormalities. Sequencing of candidate genes did not identify a genetic cause. Accurate clinical descriptions, histopathological diagnosis, and genetic investigations of patients with synechiae are lacking in the literature. Better characterization of future cases of CPLS will give new insights into its developmental causes., (Copyright © 2021 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

The vertebrate left-right axis is specified during embryogenesis by a transient organ: the left-right organizer (LRO). Species including fish, amphibians, rodents and humans deploy motile cilia in the LRO to break bilateral symmetry, while reptiles, birds, even-toed mammals and cetaceans are believed to have LROs without motile cilia. We searched for genes whose loss during vertebrate evolution follows this pattern and identified five genes encoding extracellular proteins, including a putative protease with hitherto unknown functions that we named ciliated left-right organizer metallopeptide (CIROP). Here, we show that CIROP is specifically expressed in ciliated LROs. In zebrafish and Xenopus, CIROP is required solely on the left side, downstream of the leftward flow, but upstream of DAND5, the first asymmetrically expressed gene. We further ascertained 21 human patients with loss-of-function CIROP mutations presenting with recessive situs anomalies. Our findings posit the existence of an ancestral genetic module that has twice disappeared during vertebrate evolution but remains essential for distinguishing left from right in humans., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Purpose: Biallelic hypomorphic variants in PPA2, encoding the mitochondrial inorganic pyrophosphatase 2 protein, have been recently identified in individuals presenting with sudden cardiac death, occasionally triggered by alcohol intake or a viral infection. Here we report 20 new families harboring PPA2 variants., Methods: Synthesis of clinical and molecular data concerning 34 individuals harboring five previously reported PPA2 variants and 12 novel variants, 11 of which were functionally characterized., Results: Among the 34 individuals, only 6 remain alive. Twenty-three died before the age of 2 years while five died between 14 and 16 years. Within these 28 cases, 15 died of sudden cardiac arrest and 13 of acute heart failure. One case was diagnosed prenatally with cardiomyopathy. Four teenagers drank alcohol before sudden cardiac arrest. Progressive neurological signs were observed in 2/6 surviving individuals. For 11 variants, recombinant PPA2 enzyme activities were significantly decreased and sensitive to temperature, compared to wild-type PPA2 enzyme activity., Conclusion: We expand the clinical and mutational spectrum associated with PPA2 dysfunction. Heart failure and sudden cardiac arrest occur at various ages with inter- and intrafamilial phenotypic variability, and presentation can include progressive neurological disease. Alcohol intake can trigger cardiac arrest and should be strictly avoided., (© 2021. The Author(s).)

Acrofrontofacionasal dysostosis type 1 (AFFND1) is an extremely rare disorder characterized by several dysmorphic features, skeletal abnormalities and intellectual disability, and described only in seven patients in the literature. A biallelic variant in the Neuroblastoma Amplified Sequence (NBAS) gene was recently identified in two Indian patients with AFFND1. Here we report genetic investigation of AFFND1 in the originally described Brazilian families and the identification of an extremely rare, recessively-inherited, intronic variant in the Phosphatidylinositol Glycan class B (PIGB) gene NC_000015.10 (NM_004855.4): c.795-19T > G) in the affected individuals. The PIGB gene encodes an enzyme involved in the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor, which is required for the post-translational modification of a large variety of proteins, enabling their correct cellular localization and function. Recessive variants in PIGB have previously been reported in individuals with a neurodevelopmental syndrome having partial overlap with AFFND1. In vitro assays demonstrated that the intronic variant leads to exon skipping, suggesting the Brazilian AFFND1 patients may be null for PIGB, in agreement with their severe clinical phenotype. These data increase the number of pathogenic variants in the PIGB gene, place AFFND1 among GPI deficiencies and extend the spectrum of phenotypes associated with GPI biosynthesis defects., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Although children with ADHD continue to experience impairment well into adolescence, research exploring the experiences of their parents during late adolescence is lacking. Thus, we examined changes in parenting stress and family conflict in mothers of adolescents with ADHD during the transition to early adulthood. We also explored predictors of these changes in addition to investigating differences in these trajectories due to comorbid ODD. Forty-nine mothers of adolescents with ADHD only and thirty-seven mothers of adolescents with ADHD/ODD reported on parenting stress and perceptions of family conflict at baseline (mean age = 16.88) and at 3-month, 9-month, and 15-month follow up assessments. Growth curve modeling indicated that both groups of mothers reported relative declines in parenting stress and family conflict across time. However, the mothers of adolescents with ADHD/ODD persistently reported more stress and conflict. Furthermore, decreases in family conflict were more predictive of reduced parenting stress in families of adolescents only diagnosed with ADHD. Our findings suggest that comorbid ODD is associated with parenting stress during late adolescence. Thus, interventions should focus on further reducing this stress as adolescents with ADHD/ODD transition to adulthood., Competing Interests: Conflict of Interest: Dr. Fabiano has received an investigator-initiated research grant from Shire Pharmaceuticals. The other authors declare that they have no conflict of interest.

There has been a lack of research on the third area of impairment noted in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition -"occupational functioning." It is important to understand the impact of common treatments for attention-deficit/hyperactivity disorder (ADHD) in occupational settings. Twenty individuals with ADHD between ages 16 and 25 participated in a double-blind, placebo controlled evaluation of 40 mg lisdexamfetamine dimesylate in a setting designed to approximate a restaurant workplace with associated, simulated food delivery. Outcome measures included ratings of performance, as well as behavioral productivity. Results indicated that participants completed more workplace tasks when on medication, relative to placebo. Ratings of job application quality, job interview performance, and delivery outcomes were not significantly different on medication versus placebo. These results suggest positive effects of medication in a workplace environment, but also a need for study of additional interventions to support workplace-related behavior and functioning. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

ANKRD17 is an ankyrin repeat-containing protein thought to play a role in cell cycle progression, whose ortholog in Drosophila functions in the Hippo pathway as a co-factor of Yorkie. Here, we delineate a neurodevelopmental disorder caused by de novo heterozygous ANKRD17 variants. The mutational spectrum of this cohort of 34 individuals from 32 families is highly suggestive of haploinsufficiency as the underlying mechanism of disease, with 21 truncating or essential splice site variants, 9 missense variants, 1 in-frame insertion-deletion, and 1 microdeletion (1.16 Mb). Consequently, our data indicate that loss of ANKRD17 is likely the main cause of phenotypes previously associated with large multi-gene chromosomal aberrations of the 4q13.3 region. Protein modeling suggests that most of the missense variants disrupt the stability of the ankyrin repeats through alteration of core structural residues. The major phenotypic characteristic of our cohort is a variable degree of developmental delay/intellectual disability, particularly affecting speech, while additional features include growth failure, feeding difficulties, non-specific MRI abnormalities, epilepsy and/or abnormal EEG, predisposition to recurrent infections (mostly bacterial), ophthalmological abnormalities, gait/balance disturbance, and joint hypermobility. Moreover, many individuals shared similar dysmorphic facial features. Analysis of single-cell RNA-seq data from the developing human telencephalon indicated ANKRD17 expression at multiple stages of neurogenesis, adding further evidence to the assertion that damaging ANKRD17 variants cause a neurodevelopmental disorder., (Copyright © 2021 American Society of Human Genetics. All rights reserved.)

Hirschsprung disease (HSCR) is the most frequent developmental anomaly of the enteric nervous system, with an incidence of 1 in 5000 live births. Chronic intestinal pseudo-obstruction (CIPO) is less frequent and classified as neurogenic or myogenic. Isolated HSCR has an oligogenic inheritance with RET as the major disease-causing gene, while CIPO is genetically heterogeneous, caused by mutations in smooth muscle-specific genes. Here, we describe a series of patients with developmental disorders including gastrointestinal dysmotility, and investigate the underlying molecular bases. Trio-exome sequencing led to the identification of biallelic variants in ERBB3 and ERBB2 in 8 individuals variably associating HSCR, CIPO, peripheral neuropathy, and arthrogryposis. Thorough gut histology revealed aganglionosis, hypoganglionosis, and intestinal smooth muscle abnormalities. The cell type-specific ErbB3 and ErbB2 function was further analyzed in mouse single-cell RNA sequencing data and in a conditional ErbB3-deficient mouse model, revealing a primary role for ERBB3 in enteric progenitors. The consequences of the identified variants were evaluated using quantitative real-time PCR (RT-qPCR) on patient-derived fibroblasts or immunoblot assays on Neuro-2a cells overexpressing WT or mutant proteins, revealing either decreased expression or altered phosphorylation of the mutant receptors. Our results demonstrate that dysregulation of ERBB3 or ERBB2 leads to a broad spectrum of developmental anomalies, including intestinal dysmotility.

The structure of proline prevents it from adopting an optimal position for rapid protein synthesis. Poly-proline-tract (PPT) associated ribosomal stalling is resolved by highly conserved eIF5A, the only protein to contain the amino acid hypusine. We show that de novo heterozygous EIF5A variants cause a disorder characterized by variable combinations of developmental delay, microcephaly, micrognathia and dysmorphism. Yeast growth assays, polysome profiling, total/hypusinated eIF5A levels and PPT-reporters studies reveal that the variants impair eIF5A function, reduce eIF5A-ribosome interactions and impair the synthesis of PPT-containing proteins. Supplementation with 1 mM spermidine partially corrects the yeast growth defects, improves the polysome profiles and restores expression of PPT reporters. In zebrafish, knockdown eif5a partly recapitulates the human phenotype that can be rescued with 1 µM spermidine supplementation. In summary, we uncover the role of eIF5A in human development and disease, demonstrate the mechanistic complexity of EIF5A-related disorder and raise possibilities for its treatment.

The genetic causes of multiple congenital anomalies are incompletely understood. Here, we report novel heterozygous predicted loss-of-function (LoF) and predicted damaging missense variants in the WW domain binding protein 11 (WBP11) gene in seven unrelated families with a variety of overlapping congenital malformations, including cardiac, vertebral, tracheo-esophageal, renal and limb defects. WBP11 encodes a component of the spliceosome with the ability to activate pre-messenger RNA splicing. We generated a Wbp11 null allele in mouse using CRISPR-Cas9 targeting. Wbp11 homozygous null embryos die prior to E8.5, indicating that Wbp11 is essential for development. Fewer Wbp11 heterozygous null mice are found than expected due to embryonic and postnatal death. Importantly, Wbp11 heterozygous null mice are small and exhibit defects in axial skeleton, kidneys and esophagus, similar to the affected individuals, supporting the role of WBP11 haploinsufficiency in the development of congenital malformations in humans. LoF WBP11 variants should be considered as a possible cause of VACTERL association as well as isolated Klippel-Feil syndrome, renal agenesis or esophageal atresia., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Pathogenic variants in the core spliceosome U5 small nuclear ribonucleoprotein gene EFTUD2/SNU114 cause the craniofacial disorder mandibulofacial dysostosis Guion-Almeida type (MFDGA). MFDGA-associated variants in EFTUD2 comprise large deletions encompassing EFTUD2, intragenic deletions and single nucleotide truncating or missense variants. These variants are predicted to result in haploinsufficiency by loss-of-function of the variant allele. While the contribution of deletions within EFTUD2 to allele loss-of-function are self-evident, the mechanisms by which missense variants are disease-causing have not been characterized functionally. Combining bioinformatics software prediction, yeast functional growth assays, and a minigene (MG) splicing assay, we have characterized how MFDGA missense variants result in EFTUD2 loss-of-function. Only four of 19 assessed missense variants cause EFTUD2 loss-of-function through altered protein function when modeled in yeast. Of the remaining 15 missense variants, five altered the normal splicing pattern of EFTUD2 pre-messenger RNA predominantly through exon skipping or cryptic splice site activation, leading to the introduction of a premature termination codon. Comparison of bioinformatic predictors for each missense variant revealed a disparity amongst different software packages and, in many cases, an inability to correctly predict changes in splicing subsequently determined by MG interrogation. This study highlights the need for laboratory-based validation of bioinformatic predictions for EFTUD2 missense variants., (© 2020 The Authors. Human Mutation published by Wiley Periodicals, Inc.)

Using an all-female sample, we examined trajectories of executive functioning (EF) performance from childhood through emerging adulthood-and their prediction of key emerging-adult outcomes. One hundred forty girls carefully diagnosed with attention deficit/hyperactivity disorder (ADHD) and 88 matched comparison girls were administered EF measurements assessing global EF, response inhibition, and verbal working memory during childhood ( M age = 9.5 years), adolescence ( M age = 14.1 years), the earliest years of adulthood ( M age = 19.6 years), and the end of emerging adulthood ( M age = 25.6 years). Retention rates were excellent. Hierarchical linear modeling was used to estimate growth curves for each EF measure. The linear EF slopes were then used to explore how changes in EF interacted with each participant's persistence/remission of ADHD over time to influence behavioral, emotional, and academic impairment in emerging adulthood. Although all women experienced absolute improvements in EF performance across time, women with histories of ADHD consistently lagged behind comparison women, even if their ADHD symptoms had remitted by early adulthood. However, EF performance over time did not significantly influence the link between ADHD status and (a) maternal reports of associated behavioral and emotional impairment or (b) objective measures of academic achievement. These findings indicate that EF deficits should be considered when developing and implementing treatments for ADHD through emerging adulthood. Future research should be aimed at understanding the mechanisms behind these observed trajectory differences.

The evolutionarily conserved hedgehog (Hh) pathway is essential for organogenesis and plays critical roles in postnatal tissue maintenance and renewal. A unique feature of the vertebrate Hh pathway is that signal transduction requires the primary cilium (PC) where major pathway components are dynamically enriched. These factors include smoothened (SMO) and patched, which constitute the core reception system for sonic hedgehog (SHH) as well as GLI transcription factors, the key mediators of the pathway. Here, we report bi-allelic loss-of-function variations in SMO in seven individuals from five independent families; these variations cause a wide phenotypic spectrum of developmental anomalies affecting the brain (hypothalamic hamartoma and microcephaly), heart (atrioventricular septal defect), skeleton (postaxial polydactyly, narrow chest, and shortening of long bones), and enteric nervous system (aganglionosis). Cells derived from affected individuals showed normal ciliogenesis but severely altered Hh-signal transduction as a result of either altered PC trafficking or abnormal activation of the pathway downstream of SMO. In addition, Hh-independent GLI2 accumulation at the PC tip in cells from the affected individuals suggests a potential function of SMO in regulating basal ciliary trafficking of GLI2 when the pathway is off. Thus, loss of SMO function results in abnormal PC dynamics of key components of the Hh signaling pathway and leads to a large continuum of malformations in humans., (Copyright © 2020 American Society of Human Genetics. All rights reserved.)

Behavioral parent training programs are evidence-based treatment for children with attention-deficit/hyperactivity disorder (ADHD), yet attendance in such programs is variable. Relative to mothers of children with ADHD, far less is known about fathers and what predicts their attendance in treatment. The current study aimed to explore predictors of father ( N = 171) attendance using data from four studies that tested the efficacy of behavioral parent training programs aimed specifically at fathers. A hierarchical regression was performed to test four potential predictors of attendance, including father race/ethnicity, father education level, child medication status, and father ratings of the child's oppositional defiant disorder symptoms. Father education level was determined to be a significant predictor of attendance, whereas father race/ethnicity, child medication status, and father ratings of the child's ODD behavior were not. The results suggest that future parent training interventions may need to be adapted to improve attendance from fathers of lower education levels., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

MN1 encodes a transcriptional co-regulator without homology to other proteins, previously implicated in acute myeloid leukaemia and development of the palate. Large deletions encompassing MN1 have been reported in individuals with variable neurodevelopmental anomalies and non-specific facial features. We identified a cluster of de novo truncating mutations in MN1 in a cohort of 23 individuals with strikingly similar dysmorphic facial features, especially midface hypoplasia, and intellectual disability with severe expressive language delay. Imaging revealed an atypical form of rhombencephalosynapsis, a distinctive brain malformation characterized by partial or complete loss of the cerebellar vermis with fusion of the cerebellar hemispheres, in 8/10 individuals. Rhombencephalosynapsis has no previously known definitive genetic or environmental causes. Other frequent features included perisylvian polymicrogyria, abnormal posterior clinoid processes and persistent trigeminal artery. MN1 is encoded by only two exons. All mutations, including the recurrent variant p.Arg1295* observed in 8/21 probands, fall in the terminal exon or the extreme 3' region of exon 1, and are therefore predicted to result in escape from nonsense-mediated mRNA decay. This was confirmed in fibroblasts from three individuals. We propose that the condition described here, MN1 C-terminal truncation (MCTT) syndrome, is not due to MN1 haploinsufficiency but rather is the result of dominantly acting C-terminally truncated MN1 protein. Our data show that MN1 plays a critical role in human craniofacial and brain development, and opens the door to understanding the biological mechanisms underlying rhombencephalosynapsis., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)