GestaltMML: Enhancing Rare Genetic Disease Diagnosis through Multimodal Machine Learning Combining Facial Images and Clinical Texts.

Individuals with suspected rare genetic disorders often undergo multiple clinical evaluations, imaging studies, laboratory tests and genetic tests, to find a possible answer over a prolonged period of time. Addressing this "diagnostic odyssey" thus has substantial clinical, psychosocial, and economic benefits. Many rare genetic diseases have distinctive facial features, which can be used by artificial intelligence algorithms to facilitate clinical diagnosis, in prioritizing candidate diseases to be further examined by lab tests or genetic assays, or in helping the phenotype-driven reinterpretation of genome/exome sequencing data. Existing methods using frontal facial photos were built on conventional Convolutional Neural Networks (CNNs), rely exclusively on facial images, and cannot capture non-facial phenotypic traits and demographic information essential for guiding accurate diagnoses. Here we introduce GestaltMML, a multimodal machine learning (MML) approach solely based on the Transformer architecture. It integrates facial images, demographic information (age, sex, ethnicity), and clinical notes (optionally, a list of Human Phenotype Ontology terms) to improve prediction accuracy. Furthermore, we also evaluated GestaltMML on a diverse range of datasets, including 528 diseases from the GestaltMatcher Database, several in-house datasets of Beckwith-Wiedemann syndrome (BWS, over-growth syndrome with distinct facial features), Sotos syndrome (overgrowth syndrome with overlapping features with BWS), NAA10-related neurodevelopmental syndrome, Cornelia de Lange syndrome (multiple malformation syndrome), and KBG syndrome (multiple malformation syndrome). Our results suggest that GestaltMML effectively incorporates multiple modalities of data, greatly narrowing candidate genetic diagnoses of rare diseases and may facilitate the reinterpretation of genome/exome sequencing data.

A Natural History of NAA15-related Neurodevelopmental Disorder Through Adolescence.

NAA15 is a member of the NatA N-terminal acetyltransferase complex which acts by interacting with 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 26 participants (8 females and 18 males) over time, each with a pathogenic NAA15 variant, and administered the Vineland-3 assessment to them 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 across all domains. 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 strongly correlated at the Coping subdomain, Domestic sub-domain, and Fine motor sub-domains. It is difficult to determine the strength of these correlations due to limited power. 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.

Evaluating possible maternal effect lethality and genetic background effects in Naa10 knockout mice.

Amino-terminal (Nt-) acetylation (NTA) is a common protein modification, affecting approximately 80% of all human proteins. The human essential X-linked gene, NAA10, encodes for the enzyme NAA10, which is the catalytic subunit in the N-terminal acetyltransferase A (NatA) complex. There is extensive genetic variation in humans with missense, splice-site, and C-terminal frameshift variants in NAA10. In mice, Naa10 is not an essential gene, as there exists a paralogous gene, Naa12, that substantially rescues Naa10 knockout mice from embryonic lethality, whereas double knockouts (Naa10-/Y Naa12-/-) are embryonic lethal. However, the phenotypic variability in the mice is nonetheless quite extensive, including piebaldism, skeletal defects, small size, hydrocephaly, hydronephrosis, and neonatal lethality. Here we replicate these phenotypes with new genetic alleles in mice, but we demonstrate their modulation by genetic background and environmental effects. We cannot replicate a prior report of "maternal effect lethality" for heterozygous Naa10-/X female mice, but we do observe a small amount of embryonic lethality in the Naa10-/y male mice on the inbred genetic background in this different animal facility.

Longitudinal adaptive behavioral outcomes in Ogden syndrome by seizure status and therapeutic intervention.

Ogden syndrome, also known as NAA10-related neurodevelopmental syndrome, is a rare genetic condition associated with pathogenic variants in the NAA10 N-terminal acetylation family of proteins. The condition was initially described in 2011 and is characterized by a range of neurologic symptoms, including intellectual disability and seizures, as well as developmental delays, psychiatric symptoms, congenital heart abnormalities, hypotonia, and others. Previously published articles have described the etiology and phenotype of Ogden syndrome, mostly with retrospective analyses; herein, we report prospective data concerning its progress over time. The current study involves a total of 58 distinct participants; of these, 43 caregivers were interviewed using the Vineland-3 and answered a survey regarding therapy and other questions, 10 of whom completed the Vineland-3 but did not answer the survey, and 5 participants who answered the survey but have not yet performed the Vineland-3 due to language constraints. The average age at the time of the most recent assessment was 12.4 years, with individuals ranging in age from 11 months to 40.2 years. Using Vineland-3 scores, we show decline in cognitive function over time in individuals with Ogden syndrome (n = 53). Sub-domain analysis found the decline to be present across all modalities. In addition, we describe the nature of seizures in this condition in greater detail, as well as investigate how already-available non-pharmaceutical therapies impact individuals with NAA10-related neurodevelopmental syndrome. Additional investigation between seizure and non-seizure groups showed no significant difference in adaptive behavior outcomes. A therapy investigation showed speech therapy to be the most commonly used therapy by individuals with NAA10-related neurodevelopmental syndrome, followed by occupational and physical therapy, with more severely affected individuals receiving more types of therapy than their less-severe counterparts. Early intervention analysis was only significantly effective for speech therapy, with analyses of all other therapies being non-significant. Our study portrays the decline in cognitive function over time of individuals within our cohort, independent of seizure status, and therapies being received, and highlights the urgent need for the development of effective treatments for Ogden syndrome.

Longitudinal Adaptive Behavioral Outcomes in Ogden Syndrome by Seizure Status and Therapeutic Intervention.

Ogden syndrome, also known as NAA10-related neurodevelopmental syndrome, is a rare genetic condition associated with pathogenic variants in the NAA10 N-terminal acetylation family of proteins. The condition was initially described in 2011, and is characterized by a range of neurologic symptoms, including intellectual disability and seizures, as well as developmental delays, psychiatric symptoms, congenital heart abnormalities, hypotonia and others. Previously published articles have described the etiology and phenotype of Ogden syndrome, mostly with retrospective analyses; herein, we report prospective data concerning its progress over time. Additionally, we describe the nature of seizures in this condition in greater detail, as well as investigate how already-available non-pharmaceutical therapies impact individuals with NAA10-related neurodevelopmental syndrome. Using Vineland-3 scores, we show decline in cognitive function over time in individuals with Ogden syndrome. Sub-domain analysis found the decline to be present across all modalities. Additional investigation between seizure and non-seizure groups showed no significant difference in adaptive behavior outcomes. Therapy investigation showed speech therapy to be the most commonly used therapy by individuals with NAA10-related neurodevelopmental syndrome, followed by occupational and physical therapy. with more severely affected individuals receiving more types of therapy than their less-severe counterparts. Early intervention analysis was only significantly effective for speech therapy, with analyses of all other therapies being non-significant. Our study portrays the decline in cognitive function over time of individuals within our cohort, independent of seizure status and therapies being received, and highlights the urgent need for the development of effective treatments for Ogden syndrome.

Ophthalmic Manifestations of NAA10-Related and NAA15-Related Neurodevelopmental Syndrome: Analysis of Cortical Visual Impairment and Refractive Errors.

NAA10-related and NAA15-related neurodevelopmental syndrome, otherwise known as Ogden Syndrome, is 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 mutations 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 mutations in the NAA10 cohort (54 inherited, 10 de novo; 65 missense, 2 frameshift) and 19 patients with pathogenic mutations 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 between the NAA10 and NAA15 mutations. 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.

Evaluating possible maternal effect lethality and genetic background effects in Naa10 knockout mice.

Amino-terminal (Nt-) acetylation (NTA) is a common protein modification, affecting approximately 80% of all human proteins. The human essential X-linked gene, NAA10, encodes for the enzyme NAA10, which is the catalytic subunit in the N-terminal acetyltransferase A (NatA) complex. There is extensive genetic variation in humans with missense, splice-site, and C-terminal frameshift variants in NAA10. In mice, Naa10 is not an essential gene, as there exists a paralogous gene, Naa12, that substantially rescues Naa10 knockout mice from embryonic lethality, whereas double knockouts (Naa10-/Y Naa12-/-) are embryonic lethal. However, the phenotypic variability in the mice is nonetheless quite extensive, including piebaldism, skeletal defects, small size, hydrocephaly, hydronephrosis, and neonatal lethality. Here we replicate these phenotypes with new genetic alleles in mice, but we demonstrate their modulation by genetic background and environmental effects. We cannot replicate a prior report of "maternal effect lethality" for heterozygous Naa10-/X female mice, but we do observe a small amount of embryonic lethality in the Naa10-/Y male mice on the inbred genetic background in this different animal facility.

Ocular manifestations in a cohort of 43 patients with KBG syndrome.

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.

GestaltMatcher Database - A global reference for the facial phenotypic variability of rare human diseases.

Dysmorphologists sometimes encounter challenges in recognizing disorders due to phenotypic variability influenced by factors such as age and ethnicity. Moreover, the performance of Next Generation Phenotyping Tools such as GestaltMatcher is dependent on the diversity of the training set. Therefore, we developed GestaltMatcher Database (GMDB) - a global reference for the phenotypic variability of rare diseases that complies with the FAIR-principles. We curated dysmorphic patient images and metadata from 2,224 publications, transforming GMDB into an online dynamic case report journal. To encourage clinicians worldwide to contribute, each case can receive a Digital Object Identifier (DOI), making it a citable micro-publication. This resulted in a collection of 2,312 unpublished images, partly with longitudinal data. We have compiled a collection of 10,189 frontal images from 7,695 patients representing 683 disorders. The web interface enables gene- and phenotype-centered queries for registered users (https://db.gestaltmatcher.org/). Despite the predominant European ancestry of most patients (59%), our global collaborations have facilitated the inclusion of data from frequently underrepresented ethnicities, with 17% Asian, 4% African, and 6% with other ethnic backgrounds. The analysis has revealed a significant enhancement in GestaltMatcher performance across all ethnic groups, incorporating non-European ethnicities, showcasing a remarkable increase in Top-1-Accuracy by 31.56% and Top-5-Accuracy by 12.64%. Importantly, this improvement was achieved without altering the performance metrics for European patients. GMDB addresses dysmorphology challenges by representing phenotypic variability and including underrepresented groups, enhancing global diagnostic rates and serving as a vital clinician reference database.

ITPR1-associated spinocerebellar ataxia with craniofacial features-additional evidence for germline mosaicism.

Inositol 1,4,5-triphosphate receptor type 1 (ITPR1) is an endoplasmic reticulum-bound intracellular inositol triphosphate receptor involved in the regulation of intracellular calcium. Pathogenic variants in ITPR1 are associated with spinocerebellar ataxia (SCA) types 15/16 and 29 and have recently been implicated in a facial microsomia syndrome. In this report, we present a family with three affected individuals found to have a heterozygous missense c.800C > T (predicted p.Thr267Met) who present clinically with a SCA29-like syndrome. All three individuals presented with varying degrees of ataxia, developmental delay, and apparent intellectual disability, as well as craniofacial involvement-an uncommon finding in patients with SCA29. The variant was identified using clinical exome sequencing and validated with Sanger sequencing. It is presumed to be inherited via parental germline mosaicism. We present our findings to provide additional evidence for germline mosaic inheritance of SCA29, as well as to expand the clinical phenotype of the syndrome.

Documentation and prevalence of prenatal and neonatal outcomes in a cohort of individuals with KBG syndrome.

Ankyrin Repeat Domain 11 (ANKRD11) gene mutations are associated with KBG syndrome, a developmental disability that affects multiple organ systems. The function of ANKRD11 in human growth and development is not clear, but gene knockout or mutation are lethal in mice embryos and/or pups. In addition, it plays a vital role in chromatin regulation and transcription. Individuals with KBG syndrome are often misdiagnosed or remain undiagnosed until later in life. This is largely due to KBG syndrome's varying and nonspecific phenotypes as well as a lack of accessible genetic testing and prenatal screening. This study documents perinatal outcomes for individuals with KBG syndrome. We obtained data from 42 individuals through videoconferences, medical records, and emails. 45.2% of our cohort was born by C-section, 33.3% had a congenital heart defect, 23.8% were born prematurely, 23.8% were admitted to the NICU, 14.3% were small for gestational age, and 14.3% of the families had a history of miscarriage. These rates were higher in our cohort compared to the overall population, including non-Hispanic and Hispanic populations. Other reports included feeding difficulties (21.4%), neonatal jaundice (14.3%), decreased fetal movement (7.1%), and pleural effusions in utero (4.7%). Comprehensive perinatal studies about KBG syndrome and updated documentation of its phenotypes are important in ensuring prompt diagnosis and can facilitate correct management.

Expanding the phenotypic spectrum of NAA10-related neurodevelopmental syndrome and NAA15-related neurodevelopmental syndrome.

Amino-terminal (Nt-) acetylation (NTA) is a common protein modification, affecting 80% of cytosolic proteins in humans. The human essential gene, NAA10, encodes for the enzyme NAA10, which is the catalytic subunit in the N-terminal acetyltransferase A (NatA) complex, also including the accessory protein, NAA15. The full spectrum of human genetic variation in this pathway is currently unknown. Here we reveal the genetic landscape of variation in NAA10 and NAA15 in humans. Through a genotype-first approach, one clinician interviewed the parents of 56 individuals with NAA10 variants and 19 individuals with NAA15 variants, which were added to all known cases (N = 106 for NAA10 and N = 66 for NAA15). Although there is clinical overlap between the two syndromes, functional assessment demonstrates that the overall level of functioning for the probands with NAA10 variants is significantly lower than the probands with NAA15 variants. The phenotypic spectrum includes variable levels of intellectual disability, delayed milestones, autism spectrum disorder, craniofacial dysmorphology, cardiac anomalies, seizures, and visual abnormalities (including cortical visual impairment and microphthalmia). One female with the p.Arg83Cys variant and one female with an NAA15 frameshift variant both have microphthalmia. The frameshift variants located toward the C-terminal end of NAA10 have much less impact on overall functioning, whereas the females with the p.Arg83Cys missense in NAA10 have substantial impairment. The overall data are consistent with a phenotypic spectrum for these alleles, involving multiple organ systems, thus revealing the widespread effect of alterations of the NTA pathway in humans.

Phenotypic variability and gastrointestinal manifestations/interventions for growth in NAA10-related neurodevelopmental syndrome.

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.

KBG syndrome: videoconferencing and use of artificial intelligence driven facial phenotyping in 25 new patients.

Genetic variants in Ankyrin Repeat Domain 11 (ANKRD11) and deletions in 16q24.3 are known to cause KBG syndrome, a rare syndrome associated with craniofacial, intellectual, and neurobehavioral anomalies. We report 25 unpublished individuals from 22 families with molecularly confirmed diagnoses. Twelve individuals have de novo variants, three have inherited variants, and one is inherited from a parent with low-level mosaicism. The mode of inheritance was unknown for nine individuals. Twenty are truncating variants, and the remaining five are missense (three of which are found in one family). We present a protocol emphasizing the use of videoconference and artificial intelligence (AI) in collecting and analyzing data for this rare syndrome. A single clinician interviewed 25 individuals throughout eight countries. Participants' medical records were reviewed, and data was uploaded to the Human Disease Gene website using Human Phenotype Ontology (HPO) terms. Photos of the participants were analyzed by the GestaltMatcher and DeepGestalt, Face2Gene platform (FDNA Inc, USA) algorithms. Within our cohort, common traits included short stature, macrodontia, anteverted nares, wide nasal bridge, wide nasal base, thick eyebrows, synophrys and hypertelorism. Behavioral issues and global developmental delays were widely present. Neurologic abnormalities including seizures and/or EEG abnormalities were common (44%), suggesting that early detection and seizure prophylaxis could be an important point of intervention. Almost a quarter (24%) were diagnosed with attention deficit hyperactivity disorder and 28% were diagnosed with autism spectrum disorder. Based on the data, we provide a set of recommendations regarding diagnostic and treatment approaches for KBG syndrome.

Autosomal recessive SLC30A9 variants in a proband with a cerebrorenal syndrome and no parental consanguinity.

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.

Naa12 compensates for Naa10 in mice in the amino-terminal acetylation pathway.

Amino-terminal acetylation is catalyzed by a set of N-terminal acetyltransferases (NATs). The NatA complex (including X-linked Naa10 and Naa15) is the major acetyltransferase, with 40-50% of all mammalian proteins being potential substrates. However, the overall role of amino-terminal acetylation on a whole-organism level is poorly understood, particularly in mammals. Male mice lacking Naa10 show no globally apparent in vivo amino-terminal acetylation impairment and do not exhibit complete embryonic lethality. Rather Naa10 nulls display increased neonatal lethality, and the majority of surviving undersized mutants exhibit a combination of hydrocephaly, cardiac defects, homeotic anterior transformation, piebaldism, and urogenital anomalies. Naa12 is a previously unannotated Naa10-like paralog with NAT activity that genetically compensates for Naa10. Mice deficient for Naa12 have no apparent phenotype, whereas mice deficient for Naa10 and Naa12 display embryonic lethality. The discovery of Naa12 adds to the currently known machinery involved in amino-terminal acetylation in mice.

Diagnosis of late-infantile neuronal ceroid lipofuscinosis using dried blood spot-based assay for TPPI enzyme activity: TPPI diagnostic assay from DBS.

BACKGROUND: The neuronal ceroid lipofuscinosis 2 (NCL2) or classic late-infantile neuronal ceroid lipofuscinosis (LINCL) is a neurogenetic disorder caused by mutations in the TPPI gene, which codes for the lysosomal tripeptidyl peptidase 1 (TPPI) EC 3.4.14.9. Loss of functional TPPI activity results in progressive visual and neurological symptoms starting at around 1-2 years of age causing early death. METHODS: We report a DBS-based TPPI assay that cleaves a synthetic tetrapeptide substrate generating a product that is detected by HPLC. Probands and carriers were identified with 100% accuracy (7 probands, 30 carriers, 13 controls). RESULTS: The assay detected a single TPPI activity at a lower pH towards the substrate tested. TPPI activity measurable when extracted at lower pH while inactive at neutral pH showed steady increase for at least 8 h incubation. No loss in TPPI activity was observed when DBS were stored for at least 2 weeks either in freezer, refrigerator, room temperature or 42 °C. CONCLUSION: A sequence variant causing Arg339Gln substitution in a proband had 12% TPPI. TPPI activity can be reliably measured in DBS, giving an opportunity to diagnose NCL2 at birth and refer patients for enzyme replacement or other therapies for earliest intervention, or alternatively offers a second-tier confirmatory test.

Missense variants in TAF1 and developmental phenotypes: challenges of determining pathogenicity.

We recently described a new neurodevelopmental syndrome (TAF1/MRXS33 intellectual disability syndrome) (MIM# 300966) caused by pathogenic variants involving the X-linked gene TAF1, which participates in RNA polymerase II transcription. The initial study reported eleven families, and the syndrome was defined as presenting early in life with hypotonia, facial dysmorphia, and developmental delay that evolved into intellectual disability (ID) and/or autism spectrum disorder (ASD). 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 modelling 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 (HPO) 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 TAF1/MRXS33 intellectual disability 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 genes mapping to chromosome X. This article is protected by copyright. All rights reserved.

VAC14 syndrome in two siblings with retinitis pigmentosa and neurodegeneration with brain iron accumulation.

Whole-exome sequencing was used to identify the genetic etiology of a rapidly progressing neurological disease present in two of six siblings with early childhood onset of severe progressive spastic paraparesis and learning disabilities. A homozygous mutation (c.2005G>T, p, V669L) was found in VAC14, and the clinical phenotype is consistent with the recently described VAC14-related striatonigral degeneration, childhood-onset syndrome (SNDC) (MIM#617054). However, the phenotype includes a distinct clinical presentation of retinitis pigmentosa (RP), which has not previously been reported in association with VAC14 mutations. Brain magnetic resonance imaging (MRI) revealed abnormal magnetic susceptibility in the globus pallidus, which can be seen in neurodegeneration with brain iron accumulation (NBIA). RP is a group of inherited retinal diseases with phenotypic/genetic heterogeneity, and the pathophysiologic basis of RP is not completely understood but is thought to be due to a primary retinal photoreceptor cell degenerative process. Most cases of RP are seen in isolation (nonsyndromic); this is a report of RP in two siblings with VAC14-associated syndrome, and it is suggested that a connection between RP and VAC14-associated syndrome should be explored in future studies.