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NAA10‐related (Ogden syndrome) and NAA15‐related neurodevelopmental syndrome are known to present with varying degrees of intellectual disability, hypotonia, congenital cardiac abnormalities, seizures, and delayed speech and motor development. However, the ophthalmic manifestations of NAA10 and NAA15 variants are not yet fully characterized or understood. This study analyzed the prevalence of six ophthalmic conditions (cortical visual impairment, myopia, hyperopia, strabismus, nystagmus, and astigmatism) in 67 patients with pathogenic (P) or likely pathogenic (LP) variants in the NAA10 cohort (54 inherited, 10 de novo; 65 missense, 2 frameshift) and 19 patients with (L)P variants in the NAA15 cohort (18 de novo; 8 frameshift, 4 missense, 4 nonsense, and 1 splice site). Patients were interviewed virtually or in‐person to collect a comprehensive medical history verified by medical records. These records were then analyzed to calculate the prevalence of these ophthalmic manifestations in each cohort. Analysis revealed a higher prevalence of ophthalmic conditions in our NAA10 cohort compared to existing literature (myopia 25.4% vs. 4.7%; astigmatism 37.3% vs. 13.2%; strabismus 28.4% vs. 3.8%; CVI 22.4% vs. 8.5%, respectively). No statistically significant differences were identified in the prevalence of these conditions between the NAA10 and NAA15 variants. Our study includes novel neuroimaging of 13 NAA10 and 5 NAA15 probands, which provides no clear correlation between globe size and severity of comorbid ophthalmic disease. Finally, anecdotal evidence was compiled to underscore the importance of early ophthalmologic evaluations and therapeutic interventions. [ABSTRACT FROM AUTHOR]

Ophthalmological conditions are underreported in patients with KBG syndrome, which is classically described as presenting with dental, developmental, intellectual, skeletal, and craniofacial abnormalities. This study analyzed the prevalence of four ophthalmological conditions (strabismus, astigmatism, myopia, hyperopia) in 43 patients with KBG syndrome carrying variants in ANKRD11 or deletions in 16q24.3 and compared it to the literature. Forty‐three patients were recruited via self‐referral or a private Facebook group hosted by the KBG Foundation, with 40 of them having pathogenic or likely pathogenic variants. Virtual interviews were conducted to collect a comprehensive medical history verified by medical records. From these records, data analysis was performed to calculate the prevalence of ophthalmological conditions. Out of the 40 participants with pathogenic or likely pathogenic variants, strabismus was reported in 9 (22.5%) participants, while astigmatism, myopia, and hyperopia were reported in 11 (27.5%), 6 (15.0%), and 8 (20.0%) participants, respectively. Other reported conditions include anisometropia, amblyopia, and nystagmus. When compared to the literature, the prevalence of strabismus and refractive errors is higher than other studies. However, more research is needed to determine if variants in ANKRD11 play a role in abnormal development of the visual system. In patients with established KBG syndrome, screening for misalignment or refractive errors should be done, as interventions in patients with these conditions can improve functioning and quality of life. [ABSTRACT FROM AUTHOR]

Our study of 61 children with NAA10‐related neurodevelopmental syndrome, an X‐linked disorder due to NAA10 gene variants, demonstrated a high prevalence of growth failure, with weight and height percentiles often in the failure‐to‐thrive diagnostic range; however, dramatic weight fluctuations and phenotypic variability is evidenced in the growth parameters of this population. Although never previously explored in depth, the gastrointestinal pathology associated with NAA10‐related neurodevelopmental syndrome includes feeding difficulties in infancy, dysphagia, GERD/silent reflux, vomiting, constipation, diarrhea, bowel incontinence, and presence of eosinophils on esophageal endoscopy, in order from most to least prevalent. Additionally, the gastrointestinal symptom profile for children with this syndrome has been expanded to include eosinophilic esophagitis, cyclic vomiting syndrome, Mallory Weiss tears, abdominal migraine, esophageal dilation, and subglottic stenosis. Although the exact cause of poor growth in NAA10‐related neurodevelopmental syndrome probands is unclear and the degree of contribution to this problem by GI symptomatology remains uncertain, an analysis including nine G‐tube or GJ‐tube fed probands demonstrates that G/GJ‐tubes are overall efficacious with respect to improvements in weight gain and caregiving. The choice to insert a gastrostomy or gastrojejunal tube to aid with weight gain is often a challenging decision to make for parents, who may alternatively choose to rely on oral feeding, caloric supplementation, calorie tracking, and feeding therapy. In this case, if NAA10‐related neurodevelopmental syndrome children are not tracking above the failure to thrive (FTT) range past 1 year of age despite such efforts, the treating physicians should be consulted regarding possibly undergoing G‐tube placement to avoid prolonged growth failure. If G‐tubes are not immediately inducing weight gain after insertion, recommendations could include altering formula, increasing caloric input, or exchanging a G‐tube for a GJ‐tube by means of a minimally invasive procedure. [ABSTRACT FROM AUTHOR]

An SLC30A9-associated cerebrorenal syndrome was first reported in consanguineous Bedouin kindred by Perez et al. in 2017. Although the function of the gene has not yet been fully elucidated, it may be implicated in Wnt signaling and nuclear regulation, as well as in cell and mitochondrial zinc regulation. In this research report, we present a female proband with two distinct, inherited autosomal recessive loss-of-function SLC30A9 variants from unrelated parents. To our knowledge, this is the first reported case of a possible SLC30A9-associated cerebrorenal syndrome in a nonconsanguineous family. Furthermore, a limited statistical analysis was conducted to identify possible allele frequency differences between populations. Our findings provide further support for an SLC30A9-associated cerebrorenal syndrome and may help clarify the gene's function through its possible disease association. [ABSTRACT FROM AUTHOR]

We recently described a new neurodevelopmental syndrome (TAF1/MRXS33 intellectual disability [ID] syndrome) (MIM# 300966) caused by pathogenic variants involving the X‐linked gene TATA‐box binding protein associated factor 1 (TAF1), which participates in RNA polymerase II transcription. The initial study reported 11 families, and the syndrome was defined as presenting early in life with hypotonia, facial dysmorphia, and developmental delay that evolved into ID and/or autism spectrum disorder. We have now identified an additional 27 families through a genotype‐first approach. Familial segregation analysis, clinical phenotyping, and bioinformatics were capitalized on to assess potential variant pathogenicity, and molecular modeling was performed for those variants falling within structurally characterized domains of TAF1. A novel phenotypic clustering approach was also applied, in which the phenotypes of affected individuals were classified using 51 standardized Human Phenotype Ontology terms. Phenotypes associated with TAF1 variants show considerable pleiotropy and clinical variability, but prominent among previously unreported effects were brain morphological abnormalities, seizures, hearing loss, and heart malformations. Our allelic series broadens the phenotypic spectrum of the TAF1/MRXS33 ID syndrome and the range of TAF1 molecular defects in humans. It also illustrates the challenges for determining the pathogenicity of inherited missense variants, particularly for a gene mapping to chromosome X. [ABSTRACT FROM AUTHOR]

The most important factor that complicates the work of dysmorphologists is the significant phenotypic variability of the human face. Next-Generation Phenotyping (NGP) tools that assist clinicians with recognizing characteristic syndromic patterns are particularly challenged when confronted with patients from populations different from their training data. To that end, we systematically analyzed the impact of genetic ancestry on facial dysmorphism. For that purpose, we established the GestaltMatcher Database (GMDB) as a reference dataset for medical images of patients with rare genetic disorders from around the world. We collected 10,980 frontal facial images - more than a quarter previously unpublished - from 8,346 patients, representing 581 rare disorders. Although the predominant ancestry is still European (67%), data from underrepresented populations have been increased considerably via global collaborations (19% Asian and 7% African). This includes previously unpublished reports for more than 40% of the African patients. The NGP analysis on this diverse dataset revealed characteristic performance differences depending on the composition of training and test sets corresponding to genetic relatedness. For clinical use of NGP, incorporating non-European patients resulted in a profound enhancement of GestaltMatcher performance. The top-5 accuracy rate increased by +11.29%. Importantly, this improvement in delineating the correct disorder from a facial portrait was achieved without decreasing the performance on European patients. By design, GMDB complies with the FAIR principles by rendering the curated medical data findable, accessible, interoperable, and reusable. This means GMDB can also serve as data for training and benchmarking. In summary, our study on facial dysmorphism on a global sample revealed a considerable cross ancestral phenotypic variability confounding NGP that should be counteracted by international efforts for increasing data diversity. GMDB will serve as a vital reference database for clinicians and a transparent training set for advancing NGP technology.

This study aimed to examine the adaptive functioning status and the impact of epileptic seizures on neurocognitive outcomes in KBG syndrome, a rare genetic neurodevelopmental disorder characterized by pathogenic variants in ANKRD11. A single clinician interviewed individuals and families with genetically confirmed cases of KBG syndrome. Trained professionals also conducted assessments using the Vineland-3 Adaptive Behavior Scales. The assessment covered the domains of communication, daily living skills, socialization, and maladaptive behaviors, and then compared individuals with and without epilepsy. Further comparisons were made with data from interviews and participants' medical records. Thirty-nine individuals (22 males, 17 females) with KBG syndrome, confirmed through genetic analysis, were interviewed via videoconferencing, followed by Vineland-3 assessment by trained raters. Individuals with KBG syndrome came from 36 unique families spanning 11 countries. While the KBG cohort displayed lower overall adaptive behavior composite scores compared with the average population, several members displayed standard scores at or higher than average, as well as higher scores compared with those with the neurodevelopmental disorder Ogden syndrome. Within the KBG cohort, males consistently scored lower than females across all domains, but none of these categories reached statistical significance. While the group with epilepsy exhibited overall lower scores than the nonseizure group in every category, statistical significance was only reached in the written communication subdomain. Our research provides insights that can aid in epilepsy screening and inform assessment strategies for neurocognitive functioning in those with this condition. The cohort performed overall higher than expected, with outliers existing in both directions. Although our results suggest that seizures might influence the trajectory of KBG syndrome, the approaching but overall absence of statistical significance between study groups underscores the need for a more extensive cohort to discern subtle variations in functioning., (© 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Amino-terminal (Nt-) acetylation (NTA) is a common protein modification, affecting 80% of cytosolic proteins in humans. The human essential gene, NAA10, encodes the enzyme NAA10, as the catalytic subunit for the N-terminal acetyltransferase A (NatA) complex, including the accessory protein, NAA15. The first human disease directly involving NAA10 was discovered in 2011, and it was named Ogden syndrome (OS), after the location of the first affected family residing in Ogden, Utah, USA. Since that time, other variants have been found in NAA10 and NAA15 . Here we describe the generation of 31 iPSC lines, with 16 from females and 15 from males. This cohort includes CRISPR-mediated correction to the wild-type genotype in 4 male lines, along with editing one female line to generate homozygous wild-type or mutant clones. Following the monoclonalizaiton and screening for X-chromosome activation status in female lines, 3 additional pairs of female lines, in which either the wild type allele is on the active X chromosome (Xa) or the pathogenic variant allele is on Xa, have been generated. Subsets of this cohort have been successfully used to make cardiomyocytes and neural progenitor cells (NPCs). These cell lines are made available to the community via the NYSCF Repository., 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.

NAA15 is a member of the NatA N-terminal acetyltransferase complex, which also includes the NAA10 enzymatic sub-unit. Individuals with variants in the NAA15 coding region develop NAA15 -related neurodevelopmental syndrome, which presents with a wide array of manifestations that affect the heart, brain, musculoskeletal system, and behavioral and cognitive development. We tracked a cohort of 27 participants (9 females and 18 males) over time, each with a pathogenic NAA15 variant, and administered the Vineland-3 assessment to assess their adaptive functioning. We found that the cohort performed significantly worse compared to the normalized Vineland values. On average, females performed better than males, and they performed significantly better on the Motor Domain and Fine Motor Sub-Domain portions of the assessment. Over time, females showed a decrease in adaptive functioning, with the decline being especially correlated at the Coping, Domestic, and Fine motor sub-domains. Males (after excluding one outlier) showed a moderate positive correlation between age and ABC standard score. Ultimately, additional longitudinal data should be collected to determine the validity of the between sex-differences and to better understand the change in adaptive behavioral outcomes of individuals with NAA15 -neurodevelopmental disorder as they age.

Background: NAA10 -related (Ogden Syndrome) and NAA15 -related neurodevelopmental syndromes present with varying degrees of intellectual disability, hypotonia, congenital cardiac abnormalities, seizures, and delayed speech and motor development. While there is much data on the clinical manifestations of these conditions, there are few radiologic reports describing the neuroanatomical abnormalities present on imaging., Objective: Our goal was to provide neuroimaging analyses for a subset of probands with NAA10 - and NAA15 -related neurodevelopmental symptoms and assess severity, common radiologic anomalies, and changes over time to better understand the pathophysiology of these disease processes., Materials and Methods: Neuroimaging studies from 26 probands (18 with pathogenic variants in NAA10 , 8 with pathogenic variants in NAA15 ) were collected and analyzed. Size of the cerebrum, brainstem, and cerebellum, as well as myelination, brain malformations, globus pallidus hyperintensity, brain lesions, 4th ventricle size, tegmentovermian angle, cisterna magna size, pituitary size, olfactory tract, palate arch, and choroid plexus abnormalities were analyzed. In depth medical histories were also collected on all probands, including genetic testing results and social, cognitive, and developmental history. The Vineland 3 Adaptive Behavior Scale was also administered to the parents to assess functional status of the probands., Results: On average, individuals with Ogden Syndrome had 5.7 anatomical abnormalities (standard deviation (SD) = 3.0), whereas those with NAA15 related neurodevelopmental syndrome had 2.8 (SD = 2.3) (p = .02). Probands who had more anatomical abnormalities tended to score worse on Vineland assessments, suggesting a possible correlation between the two. Structural-functional anatomic differences seen were preserved such that individuals with greater defects on, for example, motor regions of their scans tested worse on motor portions of the Vineland. Probands followed longitudinally demonstrated several changes between scans, most commonly in the cerebellum, brainstem, and degree of myelination. Such changes were only observed for probands with NAA10 variants in our cohort., Conclusion: Despite clinical imaging being reported as being predominantly "normal" during routine clinical care, this analysis of a cohort of patients with NAA10 -related (Ogden Syndrome) and NAA15 -related neurodevelopmental syndrome by one neuroradiologist has established a range of subtle abnormalities. We hope these findings guide future research and diagnostic studies for this patient population., Competing Interests: Competing Interests The authors declare that they have no competing interests or personal relationships that could have influenced the work reported in this paper.