Biallelic variants in GTF3C5, a regulator of RNA polymerase III-mediated transcription, cause a multisystem developmental disorder.

General transcription factor IIIC subunit 5 (GTF3C5) encodes transcription factor IIIC63 (TFIIIC63). It binds to DNA to recruit another transcription factor, TFIIIB, and RNA polymerase III (Pol III) to mediate the transcription of small noncoding RNAs, such as tRNAs. Here, we report four individuals from three families presenting with a multisystem developmental disorder phenotype with biallelic variants in GTF3C5. The overlapping features include growth retardation, developmental delay, intellectual disability, dental anomalies, cerebellar malformations, delayed bone age, skeletal anomalies, and facial dysmorphism. Using lymphoblastoid cell lines (LCLs) from two affected individuals, we observed a reduction in TFIIIC63 protein levels compared to control LCLs. Genome binding of TFIIIC63 protein is also reduced in LCL from one of the affected individuals. Additionally, approximately 40% of Pol III binding regions exhibited reduction in the level of Pol III occupancy in the mutant genome relative to the control, while approximately 54% of target regions showed comparable levels of Pol III occupancy between the two, indicating partial impairment of Pol III occupancy in the mutant genome. Yeasts with subject-specific variants showed temperature sensitivity and impaired growth, supporting the notion that the identified variants have deleterious effects. gtf3c5 mutant zebrafish showed developmental defects, including a smaller body, head, and eyes. Taken together, our data show that GTF3C5 plays an important role in embryonic development, and that biallelic variants in this gene cause a multisystem developmental disorder. Our study adds GTF3C5-related disorder to the growing list of genetic disorders associated with Pol III transcription machinery.

Does biological age mediate the relationship between childhood adversity and depression? Insights from the Detroit Neighborhood Health Study.

The link between childhood adversity and adulthood depression is well-established; however, the underlying mechanisms are still being explored. Recent research suggests biological age may mediate the relationship between childhood adversity and depression in later life. This study examines if biological age mediates the relationship between childhood adversity and depression symptoms using an expanded set of biological age measures in an urban population-based cohort. Data from waves 1-3 of the Detroit Neighborhood Health Study (DNHS) were used in this analysis. Questions about abuse during childhood were coded to form a childhood adversity score similar to the Adverse Childhood Experience measure. Multiple dimensions of biological age, defined as latent variables, were considered, including systemic biological age (GrimAge, PhenoAge), epigenetic age (Horvath, SkinBlood), and immune age (cytomegalovirus, herpes simplex virus type 1, C-reactive protein, interleukin-6). Depression symptoms, modeled as a latent variable, were captured through the Patient Health Questionnaire-9 (PHQ-9). Models were adjusted for age, gender, race, parent education, and past depressive symptoms. Total and direct effects of childhood adversity on depression symptoms and indirect effects mediated by biological age were estimated. For total and direct effects, we observed a dose-dependent relationship between cumulative childhood adversity and depression symptoms, with emotional abuse being particularly influential. However, contrary to prior studies, in this sample, we found few direct effects of childhood adversity on biological age or biological age on depression symptoms and no evidence of mediation through the measures of biological age considered in this study. Further research is needed to understand how childhood maltreatment experiences are embodied to influence health and wellness.

Alabama Screening and Intervention for Glaucoma and Eye Health through Telemedicine (AL-SIGHT): Baseline Results.

PURPOSE: To describe baseline results of the Alabama Screening and Intervention for Glaucoma and Eye Health through Telemedicine (AL-SIGHT) for patients at federally qualified health centers (FQHCs). Candidates were persons at risk for glaucoma-associated diseases (GAD) based on age, race/ethnicity, current diagnosis of GAD, family history, and diabetes. DESIGN: Baseline screening visit followed by remote diagnosis and referral for follow-up examinations. METHODS: Patients presenting to FQHCs who were at least 18 years of age were enrolled and underwent screening for acuity, autorefraction, intraocular pressure, visual field testing, and fundus imaging. Results were transmitted to an ophthalmologist at University of Alabama at Birmingham for diagnosis who made referrals for follow-up; follow-up attendance was noted. Questionnaires assessed participants' perspectives on screening. Primary outcomes were rates of disease detection, referral for follow-up, follow-up attendance, and participant satisfaction. RESULTS: Of the 500 participants enrolled (mean age 58 years), 45.6% were African American and 51.6% White. Remote diagnostic evaluation of ocular screening by ophthalmologist revealed 30% GAD, 6.8% diabetic retinopathy, 37.6% cataract, 68.4% refractive error, 9.2% other eye conditions. In all, 47.2% of the participants were referred for follow-up examination and for acuity 20/40 or worse or IOP ≥23 mm Hg in one or both eyes. Follow-up examination attendance was 76.7% for those referred. Participants reported being very satisfied with screening (85.8%) and with the convenience of screening in their primary care clinic (92.2%). CONCLUSIONS: The high percentage of patients diagnosed with treatable eye conditions at telemedicine screening suggest these programs in FQHCs can be effective and scalable nationwide. Attendance when referred for follow-up examination was high. Participants welcomed screenings in their communities.

Assessing efficiency of fine-mapping obesity-associated variants through leveraging ancestry architecture and functional annotation using PAGE and UKBB cohorts.

Inadequate representation of non-European ancestry populations in genome-wide association studies (GWAS) has limited opportunities to isolate functional variants. Fine-mapping in multi-ancestry populations should improve the efficiency of prioritizing variants for functional interrogation. To evaluate this hypothesis, we leveraged ancestry architecture to perform comparative GWAS and fine-mapping of obesity-related phenotypes in European ancestry populations from the UK Biobank (UKBB) and multi-ancestry samples from the Population Architecture for Genetic Epidemiology (PAGE) consortium with comparable sample sizes. In the investigated regions with genome-wide significant associations for obesity-related traits, fine-mapping in our ancestrally diverse sample led to 95% and 99% credible sets (CS) with fewer variants than in the European ancestry sample. Lead fine-mapped variants in PAGE regions had higher average coding scores, and higher average posterior probabilities for causality compared to UKBB. Importantly, 99% CS in PAGE loci contained strong expression quantitative trait loci (eQTLs) in adipose tissues or harbored more variants in tighter linkage disequilibrium (LD) with eQTLs. Leveraging ancestrally diverse populations with heterogeneous ancestry architectures, coupled with functional annotation, increased fine-mapping efficiency and performance, and reduced the set of candidate variants for consideration for future functional studies. Significant overlap in genetic causal variants across populations suggests generalizability of genetic mechanisms underpinning obesity-related traits across populations.

Recruiting Populations at Higher Risk for Glaucoma and Other Eye Diseases Experiencing Eye Health Disparities.

PURPOSE: We compared recruitment of participants at high risk for glaucoma and other eye diseases in three community-based studies designed to improve access to eye care in underserved populations in New York City, Alabama, and Michigan. METHODS: We used (1) participant data collected at enrollment (e.g. demographic, medical conditions, healthcare access, and method of hearing about study) and (2) interviews with study staff to assess effective recruitment strategies in enrolling people at high risk for eye disease. We analyzed participant data using descriptive statistics and interview data using content analysis to categorize responses to questions. RESULTS: In these community-based studies, all sites recruited greater proportions of populations with increased risk of eye disease compared to their estimates in the US population. High-risk characteristics varied based on the setting (i.e. Federally Qualified Health Centers or affordable housing buildings). Older adults represented 35% to 57%; 43% to 56% identified as Black; 1% to 40% as Hispanic/Latino; 20% to 42% reported a family history of glaucoma; 32% to 61% reported diabetes; and 50% to 67% reported high blood pressure. Social risk factors for under-utilization of eye care due to poverty included that 43% to 70% of participants had high school or lower education; 16% to 40% were employed; and 7% and 31% had no health insurance. From a qualitative perspective, active, personalized, culturally sensitive methods were most effective in recruiting participants. CONCLUSION: Implementing eye disease detection interventions in community-based settings facilitated recruiting individuals at high risk for glaucoma and other eye diseases.

Childhood and Life-Course Socioeconomic Position and Cognitive Function in the Adult Population of the Hispanic Community Health Study/Study of Latinos.

The Hispanic/Latino population experiences socioeconomic adversities across the lifespan and is at greater risk of cognitive impairment, yet little is known about the role of life-course socioeconomic position (SEP) in cognitive function in this population. Using baseline data (2008-2011) from adults (aged 45-74 years) of the Hispanic Community Health Study/Study of Latinos, we assessed the association between childhood SEP and socioeconomic mobility with cognitive function, and whether this association was mediated by midlife SEP. Childhood SEP was assessed using parental education. An index combining participants' education and household income represented midlife SEP. Socioeconomic mobility was categorized as stable low, downward or upward mobility, and stable high-SEP. Cognitive function measures were modeled using survey linear regression with inverse-probability weighting, accounting for covariates. We used mediation analysis to estimate the indirect effect of childhood SEP on cognition through midlife SEP. High childhood SEP was associated with global cognition in adulthood (coefficient for parental education beyond high school vs. less than high school = 0.26, 95% confidence interval: 0.15, 0.37). This association was partially mediated through midlife SEP (indirect effect coefficient = 0.16, 95% confidence interval: 0.15, 0.18). Low SEP through the life course was associated with the lowest cognitive function. This study provides evidence that life-course SEP influences cognitive performance in adulthood.

Beyond borders: A commentary on the benefit of promoting immigrant populations in genome-wide association studies.

Immigrants are an important part of many high-income nations, in that they contribute to the sociocultural tapestry, economic well-being, and demographic diversity of their receiving countries and communities. Yet, genomic studies to date have generally focused on non-immigrant, European-ancestry populations. Although this approach has proven fruitful in discovering and validating genomic loci, within the context of racially/ethnically diverse countries like the United States-wherein half of immigrants hail from Latin America and another quarter from Asia-this approach is insufficient. There is a persistent diversity gap in genomic research in terms of both current samples and genome-wide association studies, meaning that the field's understanding of genetic architecture and gene-environmental interactions is being hampered. In this commentary, I provide motivating examples of recent research developments related to the following: (1) how the increased ancestral diversity, such as seen among Latin American immigrants, improves power to discover and document genomic loci, (2) informs how environmental factors, such as immigration-related exposures, interact with genotypes to influence phenotypes, and (3) how inclusion can be promoted through community-engaged research programs and policies. I conclude that greater inclusion of immigrants in genomic research can move the field forward toward novel discoveries and interventions to address racial/ethnic health disparities.

A Gene-Acculturation Study of Obesity Among US Hispanic/Latinos: The Hispanic Community Health Study/Study of Latinos.

OBJECTIVE: In the United States, Hispanic/Latino adults face a high burden of obesity; yet, not all individuals are equally affected, partly due in part to this ethnic group's marked sociocultural diversity. We sought to analyze the modification of body mass index (BMI) genetic effects in Hispanic/Latino adults by their level of acculturation, a complex biosocial phenomenon that remains understudied. METHODS: Among 11,747 Hispanic/Latinos adults in the Hispanic Community Health Study/Study of Latinos aged 18 to 76 years from four urban communities (2008-2011), we a) tested our hypothesis that the effect of a genetic risk score (GRS) for increased BMI may be exacerbated by higher levels of acculturation and b) examined if GRS acculturation interactions varied by gender or Hispanic/Latino background group. All genetic modeling controlled for relatedness, age, gender, principal components of ancestry, center, and complex study design within a generalized estimated equation framework. RESULTS: We observed a GRS increase of 0.34 kg/m 2 per risk allele in weighted mean BMI. The estimated main effect of GRS on BMI varied both across acculturation level and across gender. The difference between high and low acculturation ranged from 0.03 to 0.23 kg/m 2 per risk allele, but varied across acculturation measure and gender. CONCLUSIONS: These results suggest the presence of effect modification by acculturation, with stronger effects on BMI among highly acculturated individuals and female immigrants. Future studies of obesity in the Hispanic/Latino community should account for sociocultural environments and consider their intersection with gender to better target obesity interventions.

Erratum: Ancestral diversity improves discovery and fine-mapping of genetic loci for anthropometric traits-The Hispanic/Latino Anthropometry Consortium.

[This corrects the article DOI: 10.1016/j.xhgg.2022.100099.].

Genetic and stress influences on the prevalence of hypertension among hispanics/latinos in the hispanic community health study/study of latinos (HCHS/SOL).

PURPOSE: The current study examined the effects of chronic stress and a genetic risk score on the presence of hypertension and elevated systolic blood pressure and diastolic blood pressure among Hispanics/Latinos in the target population of Hispanic Community Health Study/Study of Latinos. MATERIALS AND METHODS: Of the participants (N = 11,623) assessed during two clinic visits (Visit 1 2008-2013 & Visit 2 2014-2018), we analysed data from 7,429 adults (50.4% female), aged 18-74, who were genotyped and responded to chronic stress questionnaires. We calculated an unweighted genetic risk score using blood pressure increasing single nucleotide polymorphisms (SNPs) found to be generalisable to Hispanics/Latinos (10 SNPs). Linear and logistic regression models were used to estimate associations between chronic stress and genetic risk score and their interaction, with prevalent Visit 2 SBP or DBP, and hypertension, respectively. Models accounted for sampling weights, stratification, and cluster design. RESULTS: Chronic stress (adjusted OR = 1.18, 95%CI:1.15,1.22) and hypertension genetic risk score (adjusted OR = 1.04, 95%CI:1.01,1.07) were significantly associated with prevalent hypertension, but there was no significant interaction between the chronic stress and genetic risk score on hypertension (p = .49). genetic risk score (b = .32, 95%CI:.08, .55, R2 = .02) and chronic stress (b = .45, 95%CI:.19, .72, R2 = .11) were related to DBP, with no significant interaction (p = .62). Genetic risk score (b = .42, 95%CI:.08, .76, R2 = .01) and chronic stress (b = .80, 95%CI:.34,1.26, R2 = .11) were also related to SBP, with no significant interaction (p = .51). CONCLUSION: Results demonstrate the utility of a genetic risk score for blood pressure and are consistent with literature suggesting chronic stress has a strong, direct association with elevated blood pressure among U.S. Hispanics/Latinos.

Rare pathogenic variants in WNK3 cause X-linked intellectual disability.

PURPOSE: WNK3 kinase (PRKWNK3) has been implicated in the development and function of the brain via its regulation of the cation-chloride cotransporters, but the role of WNK3 in human development is unknown. METHOD: We ascertained exome or genome sequences of individuals with rare familial or sporadic forms of intellectual disability (ID). RESULTS: We identified a total of 6 different maternally-inherited, hemizygous, 3 loss-of-function or 3 pathogenic missense variants (p.Pro204Arg, p.Leu300Ser, p.Glu607Val) in WNK3 in 14 male individuals from 6 unrelated families. Affected individuals had ID with variable presence of epilepsy and structural brain defects. WNK3 variants cosegregated with the disease in 3 different families with multiple affected individuals. This included 1 large family previously diagnosed with X-linked Prieto syndrome. WNK3 pathogenic missense variants localize to the catalytic domain and impede the inhibitory phosphorylation of the neuronal-specific chloride cotransporter KCC2 at threonine 1007, a site critically regulated during the development of synaptic inhibition. CONCLUSION: Pathogenic WNK3 variants cause a rare form of human X-linked ID with variable epilepsy and structural brain abnormalities and implicate impaired phospho-regulation of KCC2 as a pathogenic mechanism.

Comparative Cost-effectiveness of Trabeculectomy versus MicroShunt in the US Medicare System.

PURPOSE: To assess the societal cost-utility of the MicroShunt compared with trabeculectomy for the surgical management of glaucoma in the US Medicare system. DESIGN: Cost-utility analysis using efficacy and safety results of a randomized controlled trial and other pivotal clinical trials. PARTICIPANTS: Markov model cohort of patients with open-angle glaucoma. METHODS: Open-angle glaucoma treatment costs and effects were analyzed with a deterministic model over a 1-year horizon using TreeAge software. Health states included the Hodapp-Parrish-Anderson glaucoma stages (mild, moderate, advanced, blind) and death. Both treatment arms received additional ocular hypotensive agents to control intraocular pressure (IOP). Treatment effect was measured as mean number of ocular hypotensive medications and reduction in IOP, which had a direct impact on transition probabilities between health states. Analyses of scenarios were performed with longer time horizons. One-way sensitivity and probabilistic sensitivity analyses were conducted to assess the impact of alternative model inputs. Both treatment arms were subject to reported complication rates, which were factored in the model. MAIN OUTCOME MEASURES: Incremental cost per quality-adjusted life-year (QALY) gained. RESULTS: At 1 year, the MicroShunt had an expected cost of US dollars (USD) 6318 compared with USD 4260 for trabeculectomy. MicroShunt patients gained 0.85 QALYs compared with 0.86 QALYs for trabeculectomy, resulting in a dominated incremental cost-utility ratio of USD 187 680. Dominance is a health economic term used to describe a treatment option that is both more costly and less effective than the alternative. The MicroShunt remained dominant in 1-way sensitivity analyses using best-case input parameters (including a device fee of USD 0). At a willingness-to-pay threshold of USD 50 000, the likelihood of the MicroShunt being cost-effective was 6.4%. Dominance continued in longer time horizons, up to 20 years. CONCLUSIONS: Trabeculectomy appears to be a dominant treatment strategy over the MicroShunt in the surgical management of glaucoma. More independent, long-term studies are required for the MicroShunt and other subconjunctival microstent devices to evaluate their use in clinical practice.

Heterozygous variants in PRPF8 are associated with neurodevelopmental disorders.

The pre-mRNA-processing factor 8, encoded by PRPF8, is a scaffolding component of a spliceosome complex involved in the removal of introns from mRNA precursors. Previously, heterozygous pathogenic variants in PRPF8 have been associated with autosomal dominant retinitis pigmentosa. More recently, PRPF8 was suggested as a candidate gene for autism spectrum disorder due to the enrichment of sequence variants in this gene in individuals with neurodevelopmental disorders. We report 14 individuals with various forms of neurodevelopmental conditions, found to have heterozygous, predominantly de novo, missense, and loss-of-function variants in PRPF8. These individuals have clinical features that may represent a new neurodevelopmental syndrome.

Ancestral diversity improves discovery and fine-mapping of genetic loci for anthropometric traits-The Hispanic/Latino Anthropometry Consortium.

Hispanic/Latinos have been underrepresented in genome-wide association studies (GWAS) for anthropometric traits despite their notable anthropometric variability, ancestry proportions, and high burden of growth stunting and overweight/obesity. To address this knowledge gap, we analyzed densely imputed genetic data in a sample of Hispanic/Latino adults to identify and fine-map genetic variants associated with body mass index (BMI), height, and BMI-adjusted waist-to-hip ratio (WHRadjBMI). We conducted a GWAS of 18 studies/consortia as part of the Hispanic/Latino Anthropometry (HISLA) Consortium (stage 1, n = 59,771) and generalized our findings in 9 additional studies (stage 2, n = 10,538). We conducted a trans-ancestral GWAS with summary statistics from HISLA stage 1 and existing consortia of European and African ancestries. In our HISLA stage 1 + 2 analyses, we discovered one BMI locus, as well as two BMI signals and another height signal each within established anthropometric loci. In our trans-ancestral meta-analysis, we discovered three BMI loci, one height locus, and one WHRadjBMI locus. We also identified 3 secondary signals for BMI, 28 for height, and 2 for WHRadjBMI in established loci. We show that 336 known BMI, 1,177 known height, and 143 known WHRadjBMI (combined) SNPs demonstrated suggestive transferability (nominal significance and effect estimate directional consistency) in Hispanic/Latino adults. Of these, 36 BMI, 124 height, and 11 WHRadjBMI SNPs were significant after trait-specific Bonferroni correction. Trans-ancestral meta-analysis of the three ancestries showed a small-to-moderate impact of uncorrected population stratification on the resulting effect size estimates. Our findings demonstrate that future studies may also benefit from leveraging diverse ancestries and differences in linkage disequilibrium patterns to discover novel loci and additional signals with less residual population stratification.

Clinicians' Use of Quantitative Information while Assessing the Rate of Functional Progression in Glaucoma.

PURPOSE: Clinicians use both global and point-wise information from visual fields to assess the rate of glaucomatous functional progression. We asked which objective, quantitative measures best correlated with subjective assessment by glaucoma experts. In particular, we aimed to determine how much that judgment was based on localized rates of change vs. on global indices reported by the perimeter. DESIGN: Prospective cohort study. PARTICIPANTS: Eleven academic, expert glaucoma specialists independently scored the rate of functional progression, from 1 (improvement) to 7 (very rapid progression), for a series of 5 biannual clinical printouts from 100 glaucoma or glaucoma suspect eyes of 51 participants, 20 of which were scored twice to assess repeatability. METHODS: Regression models were used to predict the average of the 11 clinicians' scores based on objective rates of change of mean deviation (MD), visual field index (VFI), pattern standard deviation (PSD), the Nth fastest progressing location, and the Nth fastest progressing of 10 anatomically defined clusters of locations after weighting by eccentricity. MAIN OUTCOME MEASURES: Correlation between the objective rates of change and the average of the 11 clinicians' scores. RESULTS: The average MD of the study eyes was -2.4 dB (range, -16.8 to +2.8 dB). The mean clinician score was highly repeatable, with an intraclass correlation coefficient of 0.95. It correlated better with the rate of change of VFI (pseudo-R2 = 0.73, 95% confidence interval [CI, 0.60-0.83]) than with MD (pseudo-R2 = 0.63, 95% CI [0.45-0.76]) or PSD (pseudo-R2 = 0.41, 95% CI [0.26-0.55]). Using point-wise information, the highest correlations were found with the fifth-fastest progressing location (pseudo-R2 = 0.71, 95% CI [0.56-0.80]) and the fastest-progressing cluster after eccentricity weighting (pseudo-R2 = 0.61, 95% CI [0.48-0.72]). Among 25 eyes with an average VFI of > 99%, the highest observed pseudo-R2 value was 0.34 (95% CI [0.16-0.61]) for PSD. CONCLUSIONS: Expert academic glaucoma specialists' assessment of the rate of change correlated best with VFI rates, except in eyes with a VFI near the ceiling of 100%. Sensitivities averaged within clusters of locations have been shown to detect change sooner, but the experts' opinions correlated more closely with global VFI. This could be because it is currently the only index for which the perimeter automatically provides a quantitative estimate of the rate of functional progression.

Clinicians' Use of Quantitative Information When Assessing the Rate of Structural Progression in Glaucoma.

PURPOSE: OCT scans contain large amounts of information, but clinicians often rely on reported layer thicknesses when assessing the rate of glaucomatous progression. We sought to determine which of these quantifications most closely relate to the subjective assessment of glaucoma experts who had all the diagnostic information available. DESIGN: Prospective cohort study. PARTICIPANTS: Eleven glaucoma specialists independently scored the rate of structural progression from a series of 5 biannual clinical OCT printouts. METHODS: A total of 100 glaucoma or glaucoma suspect eyes of 51 participants were included; 20 were scored twice to assess repeatability. Scores ranged from 1 (improvement) to 7 (very rapid progression). Generalized estimating equation linear models were used to predict the mean clinician score from the rates of change of retinal nerve fiber layer thickness (RNFLT) or minimum rim width (MRW) globally or in the most rapidly thinning of the 6 sectors. MAIN OUTCOME MEASURES: The correlation between the objective rates of change and the average of the 11 clinicians' scores. RESULTS: Average RNFLT within the series of study eyes was 79.3 µm (range, 41.4-126.6). Some 95% of individual clinician scores varied by ≤ 1 point when repeated. The mean clinician score was more strongly correlated with the rate of change of RNFLT in the most rapidly changing sector in %/year (pseudo-R2 = 0.657) than the rate of global RNFLT (0.372). The rate of MRW in the most rapidly changing sector had pseudo-R2 = 0.149. CONCLUSIONS: The rate of change of RNFLT in the most rapidly changing sector predicted experts' assessment of the rate of structural progression better than global rates or MRW. Sectoral rates may be a useful addition to current clinical printouts.

De novo loss-of-function variant in PTDSS1 is associated with developmental delay.

Heterozygous de novo missense pathogenic variants in PTDSS1 that result in gain-of-function of phosphatidylserine synthase 1 are associated with Lenz-Majewski hyperostotic dwarfism (LMHD). We identified the novel heterozygous de novo variant p.(Leu137Phe) in PTDSS1 in a child with mild-to-moderate developmental delay. Skeletal survey revealed no evidence of LMHD in this patient. Functional assessment of the p.Leu137Phe variant was performed by overexpressing the mutant protein into HEK293 cells. Following C14 -serine labeling and TLC analysis of lipids, we observed that the p.(Leu137Phe) variant displayed no catalytic activity compared to the wild-type enzyme. We conclude that p.(Leu137Phe) variant has decreased enzymatic activity and that is likely to be the etiology of the patient's symptoms given the gene's constraint in the population. This is the first report of the clinical phenotype seen in an individual with a heterozygous loss-of-function variant in PTDSS1. This phenotype is distinct from LMHD, which results from gain-of-function pathogenic variants in the same gene. Evaluation of the neurodevelopmental phenotype of additional individuals with loss-of-function variants in PTDSS1 is indicated to determine the spectrum of associated phenotypes.