Barriers to a successful healthcare transition for individuals with urea cycle disorders.

The pediatric to adult healthcare transition (HCT) is a process for individuals with chronic health conditions to gradually shift from a pediatric to an adult-oriented care system. Autonomy and self-management skills required for an individual's HCT readiness can be evaluated through the transition readiness assessment questionnaire (TRAQ). Despite general HCT preparation guidelines, little is known about the HCT experience of individuals with a urea cycle disorder (UCD). This is the first study to report the parent or guardian perception of the HCT process in children with a UCD by investigating the stages of transition readiness and transition outcome. We identify barriers to HCT readiness and planning, along with deficiencies in transition outcome for individuals with a UCD. For children that received special education services compared to those that did not, significantly lower transition readiness scores were identified in the total TRAQ score (p = 0.03) and in the domains of tracking health issues (p = 0.02), talking with providers (p = 0.03), and managing daily activities (p = 0.01). There was a lack of HCT preparation as most subjects did not have a HCT discussion with their healthcare provider before age 26. Deficiencies in HCT outcome are demonstrated by individuals with a UCD reporting delays in needed medical care and dissatisfaction with their healthcare services. Considerations for facilitating a successful HCT for individuals with a UCD include providing individualized education, appointing a transition coordinator, allowing flexibility in HCT timing, and ensuring that the individual recognizes concerning UCD symptoms and knows when to seek medical care.

Parent perspectives on disclosing a pediatric neurofibromatosis type 1 diagnosis.

Neurofibromatosis 1 (NF1) is a common genetic disorder typically diagnosed in childhood and characterized by cutaneous findings, nerve sheath tumors, skeletal abnormalities, malignancies, and developmental differences. Due to its variability, NF1 is an unpredictable condition that parents have concerns about discussing with their children. While there are publications addressing the disclosure of genetic conditions in general, no NF1-specific disclosure literature exists. To fill this gap, this mixed methods study sought to evaluate the concerns, barriers, failures, or successes parents or guardians have experienced when they have or have not chosen to tell their child(ren) about an NF1 diagnosis. Parents of children between ages 0 and 17 with a diagnosis of NF1 completed a survey and some parents were selected for an interview invitation. A total of 258 surveys were completed, and 20 parents were interviewed. Interview transcripts were categorized into disclosure and non-disclosure groups. Themes were organized into five categories based on interview questions: disclosure concerns, factors affecting disclosure/non-disclosure, approaches to disclosure, desired resources, and recommendations for disclosure. Sentiment analysis was performed on responses about the disclosure discussion itself. Results indicated that most parents (70.5%) disclosed the NF1 diagnosis to their child and overall felt it was a positive experience. Almost one-third of parents (29.5%) had not disclosed the diagnosis. A strong significance was identified between disclosure and severe presentation of NF1 (p = 0.0008). Parents in both groups shared similar concerns about discussing the diagnosis and multiple factors influenced the disclosure decision. Most parents approached disclosure as a process and emphasized the need to be honest and supportive of their child. Parents highlighted the need for more educational resources for children and guidance on how to disclose. These findings indicate that additional resources and support for parents would facilitate disclosure and the involvement of genetic counselors in the process would be beneficial.

ZMIZ1 Variants Cause a Syndromic Neurodevelopmental Disorder.

ZMIZ1 is a coactivator of several transcription factors, including p53, the androgen receptor, and NOTCH1. Here, we report 19 subjects with intellectual disability and developmental delay carrying variants in ZMIZ1. The associated features include growth failure, feeding difficulties, microcephaly, facial dysmorphism, and various other congenital malformations. Of these 19, 14 unrelated subjects carried de novo heterozygous single-nucleotide variants (SNVs) or single-base insertions/deletions, 3 siblings harbored a heterozygous single-base insertion, and 2 subjects had a balanced translocation disrupting ZMIZ1 or involving a regulatory region of ZMIZ1. In total, we identified 13 point mutations that affect key protein regions, including a SUMO acceptor site, a central disordered alanine-rich motif, a proline-rich domain, and a transactivation domain. All identified variants were absent from all available exome and genome databases. In vitro, ZMIZ1 showed impaired coactivation of the androgen receptor. In vivo, overexpression of ZMIZ1 mutant alleles in developing mouse brains using in utero electroporation resulted in abnormal pyramidal neuron morphology, polarization, and positioning, underscoring the importance of ZMIZ1 in neural development and supporting mutations in ZMIZ1 as the cause of a rare neurodevelopmental syndrome.

Parental perceptions of genetic testing for children with autism spectrum disorders.

Children with autism spectrum disorder (ASD) routinely undergo genetic testing (GT) to identify the causative genetic etiology of their ASD. As there are questions about the impact of GT beyond clinical diagnosis, we conducted a mixed methods study to assess the perceived benefits of GT by exploring factors that lead parents to pursue these tests and the benefits experienced. Respondents were part of a pretest or posttest group. The pretest group (N = 22) expressed intent to pursue GT and the posttest group (N = 32) had undergone GT and received results at least 3 months prior to completing the survey. Responses were compared between and within groups. Free text responses were coded for themes and selection questions were analyzed using Fisher's exact tests. Our results demonstrate significant differences between the groups with participants in the pretest group more likely to choose "increased access to therapies" (p = 0.026) and "improved healthcare" (p < 0.000) as reasons to pursue testing. Benefits were also significantly different with "improved healthcare" (p = 0.009), "improved access to services" (p = 0.012), and "improved access to therapies" (p = 0.003) more frequently anticipated by the pretest group than reported by the posttest group. A relationship between GT and clinical management changes was reported by 34.4-50.0% of the posttest group. Among that group, genetic result type (positive, negative, or variant of uncertain significance) was associated with differing perceived benefits of testing. Thematic analysis revealed increased knowledge and coping as reported benefits in both groups. Our findings indicate a discrepancy between parental expectations and experiences of GT. Comprehensive pretest and posttest genetic counseling are necessary to improve information retention, address potential outcomes, and set expectations of GT for parents of children with ASD.

De Novo Missense Variants in TRAF7 Cause Developmental Delay, Congenital Anomalies, and Dysmorphic Features.

TRAF7 is a multi-functional protein involved in diverse signaling pathways and cellular processes. The phenotypic consequence of germline TRAF7 variants remains unclear. Here we report missense variants in TRAF7 in seven unrelated individuals referred for clinical exome sequencing. The seven individuals share substantial phenotypic overlap, with developmental delay, congenital heart defects, limb and digital anomalies, and dysmorphic features emerging as key unifying features. The identified variants are de novo in six individuals and comprise four distinct missense changes, including a c.1964G>A (p.Arg655Gln) variant that is recurrent in four individuals. These variants affect evolutionarily conserved amino acids and are located in key functional domains. Gene-specific mutation rate analysis showed that the occurrence of the de novo variants in TRAF7 (p = 2.6 × 10-3) and the recurrent de novo c.1964G>A (p.Arg655Gln) variant (p = 1.9 × 10-8) in our exome cohort was unlikely to have occurred by chance. In vitro analyses of the observed TRAF7 mutations showed reduced ERK1/2 phosphorylation. Our findings suggest that missense mutations in TRAF7 are associated with a multisystem disorder and provide evidence of a role for TRAF7 in human development.

Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies.

N-alpha-acetylation is a common co-translational protein modification that is essential for normal cell function in humans. We previously identified the genetic basis of an X-linked infantile lethal Mendelian disorder involving a c.109T>C (p.Ser37Pro) missense variant in NAA10, which encodes the catalytic subunit of the N-terminal acetyltransferase A (NatA) complex. The auxiliary subunit of the NatA complex, NAA15, is the dimeric binding partner for NAA10. Through a genotype-first approach with whole-exome or genome sequencing (WES/WGS) and targeted sequencing analysis, we identified and phenotypically characterized 38 individuals from 33 unrelated families with 25 different de novo or inherited, dominantly acting likely gene disrupting (LGD) variants in NAA15. Clinical features of affected individuals with LGD variants in NAA15 include variable levels of intellectual disability, delayed speech and motor milestones, and autism spectrum disorder. Additionally, mild craniofacial dysmorphology, congenital cardiac anomalies, and seizures are present in some subjects. RNA analysis in cell lines from two individuals showed degradation of the transcripts with LGD variants, probably as a result of nonsense-mediated decay. Functional assays in yeast confirmed a deleterious effect for two of the LGD variants in NAA15. Further supporting a mechanism of haploinsufficiency, individuals with copy-number variant (CNV) deletions involving NAA15 and surrounding genes can present with mild intellectual disability, mild dysmorphic features, motor delays, and decreased growth. We propose that defects in NatA-mediated N-terminal acetylation (NTA) lead to variable levels of neurodevelopmental disorders in humans, supporting the importance of the NatA complex in normal human development.

Outcomes of prior authorization requests for genetic testing in outpatient pediatric genetics clinics.

PURPOSE: Genetic testing is an important diagnostic tool in pediatric genetics clinics, yet many patients face barriers to testing. We describe the outcomes of prior authorization requests (PARs) for genetic tests, one indicator of patient access to clinically recommended testing, in pediatric genetics clinics. METHODS: We retrospectively reviewed PARs for genetic tests (n = 4,535) recommended for patients <18 years of age (n = 2,798) by pediatric medical geneticists at two children's hospitals in Texas, 2017-2018. We described PAR outcomes, accompanying diagnostic codes, and diagnostic yield. RESULTS: The majority (79.9%) of PARs received a favorable outcome. PARs submitted to public payers were more likely to receive a favorable outcome compared with private payers (85.5% vs. 70.3%, respectively; p < 0.001). No diagnostic codes were associated with higher likelihood of PAR approval for exome sequencing. Among the 2,685 tests approved and completed, 522 (19.4%) resulted in a diagnosis. CONCLUSION: Though there was a high PAR approval rate, our findings suggest that insurance coverage remains one barrier to genetic testing. When completed, genetic testing had a high yield in our sample. Further evidence of clinical utility and development of clinical practice guidelines may inform payer medical policy development and improve access to testing in the future.

Intraperitoneal bladder rupture in a young child with vascular Ehlers-Danlos syndrome.

In this report, we present the case of a 3-year-old child with vascular Ehlers-Danlos syndrome (vEDS) previously known as Ehlers-Danlos syndrome type IV. After experiencing a minor traumatic injury to the abdomen, consisting of falling over a bathroom stool on the way to the restroom with a full bladder, the child developed acute abdominal pain. He was found to have an intraperitoneal bladder rupture that was successfully repaired with management techniques tailored to his known diagnosis of vEDS. While tissue fragility and internal organ rupture occurring with minor trauma are known complications of vEDS, this is the first case in the literature of a bladder rupture in a child with vEDS with a confirmed variant in the COL3A1 gene, to our knowledge. This case broadens the clinical presentation of vEDS, demonstrates that children can have life-threatening organ rupture at a young age, and may alert providers to consider this diagnosis when a child presents with bladder rupture.

Retrospective Diagnosis of Ataxia-Telangiectasia in an Adolescent Patient With a Remote History of T-Cell Leukemia.

Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder characterized by progressive cerebellar degeneration that is typically diagnosed in early childhood. A-T is associated with a predisposition to malignancies, particularly lymphoid tumors in childhood and early adulthood. An adolescent girl with minimal neurologic symptoms was diagnosed with A-T 8 years after completing therapy for T-cell acute lymphoblastic leukemia, following a diagnosis of ATM-mutated breast cancer in her mother. We highlight the importance of recognizing ATM mutations in T-cell acute lymphoblastic leukemia, appreciating the phenotypic heterogeneity of A-T, and defining optimal cancer screening in A-T patients.

BAZ2B haploinsufficiency as a cause of developmental delay, intellectual disability, and autism spectrum disorder.

The bromodomain adjacent to zinc finger 2B gene (BAZ2B) encodes a protein involved in chromatin remodeling. Loss of BAZ2B function has been postulated to cause neurodevelopmental disorders. To determine whether BAZ2B deficiency is likely to contribute to the pathogenesis of these disorders, we performed bioinformatics analyses that demonstrated a high level of functional convergence during fetal cortical development between BAZ2B and genes known to cause autism spectrum disorder (ASD) and neurodevelopmental disorder. We also found an excess of de novo BAZ2B loss-of-function variants in exome sequencing data from previously published cohorts of individuals with neurodevelopmental disorders. We subsequently identified seven additional individuals with heterozygous deletions, stop-gain, or de novo missense variants affecting BAZ2B. All of these individuals have developmental delay (DD), intellectual disability (ID), and/or ASD. Taken together, our findings suggest that haploinsufficiency of BAZ2B causes a neurodevelopmental disorder, whose cardinal features include DD, ID, and ASD.

Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype-phenotype study in neurofibromatosis type 1.

We report 281 individuals carrying a pathogenic recurrent NF1 missense variant at p.Met1149, p.Arg1276, or p.Lys1423, representing three nontruncating NF1 hotspots in the University of Alabama at Birmingham (UAB) cohort, together identified in 1.8% of unrelated NF1 individuals. About 25% (95% confidence interval: 20.5-31.2%) of individuals heterozygous for a pathogenic NF1 p.Met1149, p.Arg1276, or p.Lys1423 missense variant had a Noonan-like phenotype, which is significantly more compared with the "classic" NF1-affected cohorts (all p < .0001). Furthermore, p.Arg1276 and p.Lys1423 pathogenic missense variants were associated with a high prevalence of cardiovascular abnormalities, including pulmonic stenosis (all p < .0001), while p.Arg1276 variants had a high prevalence of symptomatic spinal neurofibromas (p < .0001) compared with "classic" NF1-affected cohorts. However, p.Met1149-positive individuals had a mild phenotype, characterized mainly by pigmentary manifestations without externally visible plexiform neurofibromas, symptomatic spinal neurofibromas or symptomatic optic pathway gliomas. As up to 0.4% of unrelated individuals in the UAB cohort carries a p.Met1149 missense variant, this finding will contribute to more accurate stratification of a significant number of NF1 individuals. Although clinically relevant genotype-phenotype correlations are rare in NF1, each affecting only a small percentage of individuals, together they impact counseling and management of a significant number of the NF1 population.

A Recurrent De Novo Nonsense Variant in ZSWIM6 Results in Severe Intellectual Disability without Frontonasal or Limb Malformations.

A recurrent de novo missense variant within the C-terminal Sin3-like domain of ZSWIM6 was previously reported to cause acromelic frontonasal dysostosis (AFND), an autosomal-dominant severe frontonasal and limb malformation syndrome, associated with neurocognitive and motor delay, via a proposed gain-of-function effect. We present detailed phenotypic information on seven unrelated individuals with a recurrent de novo nonsense variant (c.2737C>T [p.Arg913Ter]) in the penultimate exon of ZSWIM6 who have severe-profound intellectual disability and additional central and peripheral nervous system symptoms but an absence of frontonasal or limb malformations. We show that the c.2737C>T variant does not trigger nonsense-mediated decay of the ZSWIM6 mRNA in affected individual-derived cells. This finding supports the existence of a truncated ZSWIM6 protein lacking the Sin3-like domain, which could have a dominant-negative effect. This study builds support for a key role for ZSWIM6 in neuronal development and function, in addition to its putative roles in limb and craniofacial development, and provides a striking example of different variants in the same gene leading to distinct phenotypes.

Evaluation and classification of severity for 176 genes on an expanded carrier screening panel.

BACKGROUND: Disease severity is important when considering genes for inclusion on reproductive expanded carrier screening (ECS) panels. We applied a validated and previously published algorithm that classifies diseases into four severity categories (mild, moderate, severe, and profound) to 176 genes screened by ECS. Disease traits defining severity categories in the algorithm were then mapped to four severity-related ECS panel design criteria cited by the American College of Obstetricians and Gynecologists (ACOG). METHODS: Eight genetic counselors (GCs) and four medical geneticists (MDs) applied the severity algorithm to subsets of 176 genes. MDs and GCs then determined by group consensus how each of these disease traits mapped to ACOG severity criteria, enabling determination of the number of ACOG severity criteria met by each gene. RESULTS: Upon consensus GC and MD application of the severity algorithm, 68 (39%) genes were classified as profound, 71 (40%) as severe, 36 (20%) as moderate, and one (1%) as mild. After mapping of disease traits to ACOG severity criteria, 170 out of 176 genes (96.6%) were found to meet at least one of the four criteria, 129 genes (73.3%) met at least two, 73 genes (41.5%) met at least three, and 17 genes (9.7%) met all four. CONCLUSION: This study classified the severity of a large set of Mendelian genes by collaborative clinical expert application of a trait-based algorithm. Further, it operationalized difficult to interpret ACOG severity criteria via mapping of disease traits, thereby promoting consistency of ACOG criteria interpretation.

Biallelic mutations in the ferredoxin reductase gene cause novel mitochondriopathy with optic atrophy.

Iron-sulfur (Fe-S) clusters are ubiquitous cofactors essential to various cellular processes, including mitochondrial respiration, DNA repair, and iron homeostasis. A steadily increasing number of disorders are being associated with disrupted biogenesis of Fe-S clusters. Here, we conducted whole-exome sequencing of patients with optic atrophy and other neurological signs of mitochondriopathy and identified 17 individuals from 13 unrelated families with recessive mutations in FDXR, encoding the mitochondrial membrane-associated flavoprotein ferrodoxin reductase required for electron transport from NADPH to cytochrome P450. In vitro enzymatic assays in patient fibroblast cells showed deficient ferredoxin NADP reductase activity and mitochondrial dysfunction evidenced by low oxygen consumption rates (OCRs), complex activities, ATP production and increased reactive oxygen species (ROS). Such defects were rescued by overexpression of wild-type FDXR. Moreover, we found that mice carrying a spontaneous mutation allelic to the most common mutation found in patients displayed progressive gait abnormalities and vision loss, in addition to biochemical defects consistent with the major clinical features of the disease. Taken together, these data provide the first demonstration that germline, hypomorphic mutations in FDXR cause a novel mitochondriopathy and optic atrophy in humans.

De Novo Truncating Variants in SON Cause Intellectual Disability, Congenital Malformations, and Failure to Thrive.

SON is a key component of the spliceosomal complex and a critical mediator of constitutive and alternative splicing. Additionally, SON has been shown to influence cell-cycle progression, genomic integrity, and maintenance of pluripotency in stem cell populations. The clear functional relevance of SON in coordinating essential cellular processes and its presence in diverse human tissues suggests that intact SON might be crucial for normal growth and development. However, the phenotypic effects of deleterious germline variants in SON have not been clearly defined. Herein, we describe seven unrelated individuals with de novo variants in SON and propose that deleterious variants in SON are associated with a severe multisystem disorder characterized by developmental delay, persistent feeding difficulties, and congenital malformations, including brain anomalies.

Biallelic loss-of-function P4HTM gene variants cause hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities (HIDEA syndrome).

PURPOSE: A new syndrome with hypotonia, intellectual disability, and eye abnormalities (HIDEA) was previously described in a large consanguineous family. Linkage analysis identified the recessive disease locus, and genome sequencing yielded three candidate genes with potentially pathogenic biallelic variants: transketolase (TKT), transmembrane prolyl 4-hydroxylase (P4HTM), and ubiquitin specific peptidase 4 (USP4). However, the causative gene remained elusive. METHODS: International collaboration and exome sequencing were used to identify new patients with HIDEA and biallelic, potentially pathogenic, P4HTM variants. Segregation analysis was performed using Sanger sequencing. P4H-TM wild-type and variant constructs without the transmembrane region were overexpressed in insect cells and analyzed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and western blot. RESULTS: Five different homozygous or compound heterozygous pathogenic P4HTM gene variants were identified in six new and six previously published patients presenting with HIDEA. Hypoventilation, obstructive and central sleep apnea, and dysautonomia were identified as novel features associated with the phenotype. Characterization of three of the P4H-TM variants demonstrated yielding insoluble protein products and, thus, loss-of-function. CONCLUSIONS: Biallelic loss-of-function P4HTM variants were shown to cause HIDEA syndrome. Our findings enable diagnosis of the condition, and highlight the importance of assessing the need for noninvasive ventilatory support in patients.

Congenital hyperinsulinism as the presenting feature of Kabuki syndrome: clinical and molecular characterization of 9 affected individuals.

PURPOSE: Describe the clinical and molecular findings of patients with Kabuki syndrome (KS) who present with hypoglycemia due to congenital hyperinsulinism (HI), and assess the incidence of KS in patients with HI. METHODS: We documented the clinical features and molecular diagnoses of 9 infants with persistent HI and KS via a combination of sequencing and copy-number profiling methodologies. Subsequently, we retrospectively evaluated 100 infants with HI lacking a genetic diagnosis, for causative variants in KS genes. RESULTS: Molecular diagnoses of KS were established by identification of pathogenic variants in KMT2D (n = 5) and KDM6A (n = 4). Among the 100 infants with HI of unknown genetic etiology, a KS diagnosis was uncovered in one patient. CONCLUSIONS: The incidence of HI among patients with KS may be higher than previously reported, and KS may account for as much as 1% of patients diagnosed with HI. As the recognition of dysmorphic features associated with KS is challenging in the neonatal period, we propose KS should be considered in the differential diagnosis of HI. Since HI in patients with KS is well managed medically, a timely recognition of hyperinsulinemic episodes will improve outcomes, and prevent aggravation of the preexisting mild to moderate intellectual disability in KS.

Correction: "Congenital hyperinsulinism as the presenting feature of Kabuki syndrome: clinical and molecular characterization of 10 affected individuals".

The author Diva D. De Leon was incorrectly listed as instead of Diva D. De Leó-Critchlow in the original version of this paper.

Correction: Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype-phenotype correlation.

A correction has been published to this Article. The PDF and HTML have been updated accordingly.

Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype-phenotype correlation.

PURPOSE: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors. METHODS: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study. RESULTS: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_2972del. CONCLUSION: We demonstrate that individuals with the NF1 p.Met992del pathogenic variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation in these individuals and will require specialized care.