Development of webcam-collected and artificial-intelligence-derived social and cognitive performance measures for neurodevelopmental genetic syndromes

This study focused on the development and initial psychometric evaluation of a set of online, webcam-collected, and artificial intelligence-derived patient performance measures for neurodevelopmental genetic syndromes (NDGS). Initial testing and qualitative input was used to develop four stimulus paradigms capturing social and cognitive processes, including social attention, receptive vocabulary, processing speed, and single-word reading. The paradigms were administered to a sample of 375 participants, including 163 with NDGS, 56 with idiopathic neurodevelopmental disability (NDD), and 156 neurotypical controls. Twelve measures were created from the four stimulus paradigms. Valid completion rates varied from 87 to 100% across measures, with lower but adequate completion rates in participants with intellectual disability. Adequate to excellent internal consistency reliability (α = 0.67 to 0.95) was observed across measures. Test–retest reproducibility at 1-month follow-up and stability at 4-month follow-up was fair to good (r = 0.40–0.73) for 8 of the 12 measures. All gaze-based measures showed evidence of convergent and discriminant validity with parent-report measures of other cognitive and behavioral constructs. Comparisons across NDGS groups revealed distinct patterns of social and cognitive functioning, including people with PTEN mutations showing a less impaired overall pattern and people with SYNGAP1 mutations showing more attentional, processing speed, and social processing difficulties relative to people with NFIX mutations. Webcam-collected performance measures appear to be a reliable and potentially useful method for objective characterization and monitoring of social and cognitive processes in NDGS and idiopathic NDD. Additional validation work, including more detailed convergent and discriminant validity analyses and examination of sensitivity to change, is needed to replicate and extend these observations.     

Missense variant in SRCAP with distinct DNA methylation signature associated with non-FLHS SRCAP-related neurodevelopmental disorder

Floating-Harbor syndrome (FLHS) is a neurodevelopmental disorder (NDD) caused by truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein gene (SRCAP). Truncating variants proximal to this location in SRCAP result in a non-FLHS SRCAP-associated NDD; an overlapping but distinct NDD characterized by developmental delay with or without intellectual disability (ID), hypotonia, normal stature, and behavioral and psychiatric issues. Here, we report a young woman who initially presented in childhood with significant delays in speech and mild ID. In young adulthood, she developed schizophrenia. On physical examination, she had facial features suggestive of 22q11 deletion syndrome. After non-diagnostic chromosomal microarray and trio exome sequencing (ES), a re-analysis of trio ES data identified a de novo missense variant in SRCAP that was proximal to the FLHS critical region. Subsequent DNA methylation studies showed the unique methylation signature associated with pathogenic sequence variants in non-FLHS SRCAP-related NDD. This clinical report describes an individual with non-FLHS SRCAP-related NDD caused by an SRCAP missense variant, and it also demonstrates the clinical utility of ES re-analysis and DNA methylation analysis for undiagnosed patients, in particular, those with variants of uncertain significance.     

Positive effects of short course androgen therapy on the neurodevelopmental outcome in boys with 47,XXY syndrome at 36 and 72 months of age

The effects of early androgen treatment on neurodevelopmental performance in pre‐pubertal boys with 47,XXY have not been well investigated. The influence of hormones on brain development in humans suggests that a positive effect on neurodevelopmental outcome in young boys with XXY may be plausible with hormone replacement therapy. The aim of the study was to investigate retrospectively if an early course of androgen treatment (three injections of testosterone enanthate, 25 mg, each) had an impact on specific domains of neurodevelopmental function in boys with 47,XXY at 36 and 72 months of age. One hundred one boys with a karyotype of 47,XXY had neurodevelopmental assessments. The retrospective chart review resulted in one group (n = 34) who had received androgen treatment during infancy and the second group was untreated (N = 67). Statistical analysis was completed to determine if there was a positive effect from treatment observed at 36 and at 72 months on multiple domains of development. There were significant differences in multiple cognitive domains in the group who received androgen treatment, including multiple measures of language, intellectual, and neuromotor skills. Improved function was observed in neurodevelopmental outcome in boys with 47,XXY at 36 and 72 months who had been treated with a short course of androgen treatment in infancy. Continued research is underway to expand our understanding of the relationship of androgen, brain function, and neurobehavioral and neurodevelopmental outcome in boys with 47,XXY. © 2013 Wiley Periodicals, Inc.     

A validation of the Experiences in Close Relationships-Relationship Structures scale (ECR-RS) in adolescents

Emerging evidence points toward a two-dimensional attachment construct: avoidance and anxiety. The Experiences in Close Relationships-Relationship Structures scale (ECR-RS; Fraley, Heffernan, Vicary, & Brumbaugh, 2011) is a questionnaire assessing two-dimensional relationship-specific attachment structures in adults and, hence, moves beyond the traditional focus on romantic relationships. The present article explored the psychometric abilities of the ECR-RS across parental and best friend domains in a sample of 15 to 18-year-olds (n = 1999). Two oblique factors were revealed across domains, exhibiting satisfactory construct validity, including factor-specific links to the model of adult attachment (Bartholomew & Horowitz, 1991), and independent factor discrimination between subgroups. A robust validation supports the application of the ECR-RS to assessing relationship-specific adolescent attachment structures.     

The performance of genome sequencing as a first-tier test for neurodevelopmental disorders

Genome sequencing (GS) can identify novel diagnoses for patients who remain undiagnosed after routine diagnostic procedures. We tested whether GS is a better first-tier genetic diagnostic test than current standard of care (SOC) by assessing the technical and clinical validity of GS for patients with neurodevelopmental disorders (NDD). We performed both GS and exome sequencing in 150 consecutive NDD patient-parent trios. The primary outcome was diagnostic yield, calculated from disease-causing variants affecting exonic sequence of known NDD genes. GS (30%, n = 45) and SOC (28.7%, n = 43) had similar diagnostic yield. All 43 conclusive diagnoses obtained with SOC testing were also identified by GS. SOC, however, required integration of multiple test results to obtain these diagnoses. GS yielded two more conclusive diagnoses, and four more possible diagnoses than ES-based SOC (35 vs. 31). Interestingly, these six variants detected only by GS were copy number variants (CNVs). Our data demonstrate the technical and clinical validity of GS to serve as routine first-tier genetic test for patients with NDD. Although the additional diagnostic yield from GS is limited, GS comprehensively identified all variants in a single experiment, suggesting that GS constitutes a more efficient genetic diagnostic workflow.Subject terms: Neurodevelopmental disorders, DNA sequencing, Genetic techniques, Genomic analysis, Genetics research     

Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders

PurposeFor neurodevelopmental disorders (NDDs), etiological evaluation can be a diagnostic odyssey involving numerous genetic tests, underscoring the need to develop a streamlined algorithm maximizing molecular diagnostic yield for this clinical indication. Our objective was to compare the yield of exome sequencing (ES) with that of chromosomal microarray (CMA), the current first-tier test for NDDs.MethodsWe performed a PubMed scoping review and meta-analysis investigating the diagnostic yield of ES for NDDs as the basis of a consensus development conference. We defined NDD as global developmental delay, intellectual disability, and/or autism spectrum disorder. The consensus development conference included input from genetics professionals, pediatric neurologists, and developmental behavioral pediatricians.ResultsAfter applying strict inclusion/exclusion criteria, we identified 30 articles with data on molecular diagnostic yield in individuals with isolated NDD, or NDD plus associated conditions (such as Rett-like features). Yield of ES was 36% overall, 31% for isolated NDD, and 53% for the NDD plus associated conditions. ES yield for NDDs is markedly greater than previous studies of CMA(15–20%).ConclusionOur review demonstrates that ES consistently outperforms CMA for evaluation of unexplained NDDs. We propose a diagnostic algorithm placing ES at the beginning of the evaluation of unexplained NDDs.     

Neurodevelopmental and other psychiatric disorders in 22q11.2 deletion syndrome from childhood to adult age: Prospective longitudinal study of 100 individuals

The 22q11.2 deletion syndrome (22q11.2DS), affects physical as well as cognitive and emotional functioning with increased risk for psychiatric and behavioral problems. This longitudinal study of 79 individuals (18–50 years) with 22q11.2DS investigated neurodevelopmental (NDD) and psychiatric disorders in adulthood, evaluated the stability of childhood diagnoses over time, and examined associations between clinical characteristics in childhood/adolescence and diagnostic outcome in adult age. Examination using validated instruments for cognitive, psychiatric, and global functional problems in the context of an in-depth clinical evaluation found adult age stability of NDD diagnoses made in childhood, however, rates increased at follow-up. Rates of anxiety, mood, and psychotic disorders were high, with a majority meeting diagnostic criteria for one or more psychiatric disorder. The rate of psychotic disorders was much lower compared to many other studies. Variability in functioning at follow-up was primarily associated with intellectual ability at T1. The findings obtained highlight the increased risk of NDD and psychiatric problems and of cognitive impairment and reduced levels of global functioning over time. Results emphasize the importance of clinical follow-up to enable appropriate support for the promotion of optimal health along with a need for future research on effective interventions and treatment strategies.     

Clinical versus automated assessments of morphological variants in twins with and without neurodevelopmental disorders

Physical examinations are recommended as part of a comprehensive evaluation for individuals with neurodevelopmental disorders (NDDs), such as autism spectrum disorder (ASD) and attention–deficit/hyperactivity disorder. These examinations should include assessment for morphological variants. Previous studies have shown an increase in morphological variants in individuals with NDDs, particularly ASD, and that these variants may be present in greater amounts in individuals with genetic alterations. Unfortunately, assessment for morphological variants can be subjective and time‐consuming, and require a high degree of clinical expertise. Therefore, objective, automated methods of morphological assessment are desirable. This study compared the use of Face2Gene, an automated tool to explore facial morphological variants, to clinical consensus assessment, using a cohort of N = 290 twins enriched for NDDs (n = 135 with NDD diagnoses). Agreement between automated and clinical assessments were satisfactory to complete (78.3–100%). In our twin sample, individuals with NDDs did not have greater numbers of facial morphological variants when compared to those with typical development, nor when controlling for shared genetic and environmental factors within twin pairs. Common facial morphological variants in those with and without NDDs were similar and included thick upper lip vermilion, abnormality of the nasal tip, long face, and upslanted palpebral fissure. We conclude that although facial morphological variants can be assessed reliably in NDDs with automated tools like Face2Gene, clinical utility is limited when just exploring the facial region. Therefore, currently, automated assessments may best complement, rather than replace, in‐person clinical assessments.     

PTEN Hamartoma tumor syndrome in childhood: A review of the clinical literature

PTEN hamartoma tumor syndrome (PHTS) is a highly variable autosomal dominant condition associated with intellectual disability, overgrowth, and tumor predisposition phenotypes, which often overlap. PHTS incorporates a number of historical clinical presentations including Bannayan‐Riley‐Ruvalcaba syndrome, Cowden syndrome, and a macrocephaly‐autism/developmental delay syndrome. Many reviews in the literature focus on PHTS as an adult hamartoma and malignancy predisposition condition. Here, we review the current literature with a focus on pediatric presentations. The review starts with a summary of the main conditions encompassed within PHTS. We then discuss PHTS diagnostic criteria, and clinical features. We briefly address rarer PTEN associations, and the possible role of mTOR inhibitors in treatment. We acknowledge the limited understanding of the natural history of childhood‐onset PHTS as a cancer predisposition syndrome and present a summary of important management considerations.     

Looking for the hidden mutation: Bannayan–Riley–Ruvalcaba syndrome caused by constitutional and mosaic 10q23 microdeletions involving PTEN and BMPR1A

The PTEN hamartoma tumor syndrome (PHTS) is caused by heterozygous germline variants in PTEN. Here, we report two unrelated patients with juvenile polyposis, macrocephaly, intellectual disability, and hyperpigmented skin macules. Both patients were clinically suspected for the Bannayan–Riley–Ruvalcaba syndrome (BRRS), a PHTS subentity. By array‐CGH analysis, we identified an interstitial 10q23.1q23.3 deletion in a buccal mucosa sample of Patient 1 that encompassed PTEN, BMPR1A, and KLLN, among others. In contrast, neither sequencing nor array‐CGH analysis identified a pathogenic variant in PTEN or BMPR1A in a blood sample of Patient 2. However, in a surgical specimen of the thyroid gland high‐level mosaicism for a 10q23.2q23.3 deletion was observed. Additionally, the pathogenic PTEN variant c.956_959delCTTT p.(Thr319LysfsTer24) was detected in his thyroid tissue. The frame shift variant was neither detected in the patient's blood nor in his buccal mucosa sample. Low‐level mosaicism for the microdeletion was identified in a buccal swap sample, and reanalysis of the blood sample suggested marginal‐level mosaicism for deletion. The 10q23.2q23.3 deletion mosaicism was also identified in a subsequently resected colonic polyp. Thus, in both cases, the diagnosis of a 10q23 deletion syndrome, which clinically presented as BRRS, was established. Overall, the study expands the BRRS spectrum and highlights the relevance of considering mosaicism in PHTS. We conclude that in all patients with a clear clinical suspicion of PHTS, in which genetic analyses of DNA from blood and buccal swap samples fail to identify causative genetic variants, genetic analyses of additional tissues are recommended.     

Targeted gene sequencing in 6994 individuals with neurodevelopmental disorder with epilepsy

PurposeWe aimed to gain insight into frequencies of genetic variants in genes implicated in neurodevelopmental disorder with epilepsy (NDD+E) by investigating large cohorts of patients in a diagnostic setting.MethodsWe analyzed variants in NDD+E using epilepsy gene panel sequencing performed between 2013 and 2017 by two large diagnostic companies. We compared variant frequencies in 6994 panels with another 8588 recently published panels as well as exome-wide de novo variants in 1942 individuals with NDD+E and 10,937 controls.ResultsGenes with highest frequencies of ultrarare variants in NDD+E comprised SCN1A, KCNQ2, SCN2A, CDKL5, SCN8A, and STXBP1, concordant with the two other epilepsy cohorts we investigated. In only 46% of the analyzed 262 dominant and X-linked panel genes ultrarare variants in patients were reported. Among genes with contradictory evidence of association with epilepsy, CACNB4, CLCN2, EFHC1, GABRD, MAGI2, and SRPX2 showed equal frequencies in cases and controls.ConclusionWe show that improvement of panel design increased diagnostic yield over time, but panels still display genes with low or no diagnostic yield. With our data, we hope to improve current diagnostic NDD+E panel design and provide a resource of ultrarare variants in individuals with NDD+E to the community.     

Analysis of prevalence and degree of macrocephaly in patients with germline PTEN mutations and of brain weight in Pten knock-in murine model

PTEN Hamartoma Tumour Syndrome (PHTS) includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), and other conditions resulting from germline mutation of the PTEN tumour suppressor gene. Although macrocephaly, presumably due to megencephaly, is found in both CS and BRRS, the prevalence and degree have not been formally assessed in PHTS. We evaluated head size in a prospective nested series of 181 patients found to have pathogenic germline PTEN mutations. Clinical data including occipital-frontal circumference (OFC) measurement were requested for all participants. Macrocephaly was present in 94% of 161 evaluable PHTS individuals. In patients ≤ 18 years, mean OFC was +4.89 standard deviations (SD) above the population mean with no difference between genders (P = 0.7). Among patients >18 years, average OFC was 60.0 cm in females and 62.8 cm in males (P < 0.0001). To systematically determine whether macrocephaly was due to megencephaly, we examined Pten(M3M4) missense mutant mice generated and maintained on mixed backgrounds. Mice were killed at various ages, brains were dissected out and weighed. Average brain weight for Pten(M3M4) homozygous mice (N = 15) was 1.02 g compared with 0.57 g for heterozygous mice (N = 29) and 0.49 g for wild-type littermates (N = 24) (P < 0.0001). Macrocephaly, secondary to megencephaly, is an important component of PHTS and more prevalent than previously appreciated. Patients with PHTS have increased risks for breast and thyroid cancers, and early diagnosis is key to initiating timely screening to reduce patient morbidity and mortality. Clinicians should consider germline PTEN testing at an early point in the diagnostic work-up for patients with extreme macrocephaly.     

Brain morphological analysis in PTEN hamartoma tumor syndrome

PTEN hamartoma tumor syndrome (PHTS) is a spectrum of hereditary cancer syndromes caused by germline mutations in PTEN. PHTS is of high interest, because of its high rate of neurological comorbidities including macrocephaly, autism spectrum disorder, and intellectual dysfunction. Since detailed brain morphology and connectivity of PHTS remain unclear, we quantitatively evaluated brain magnetic resonance imaging (MRI) in PHTS. Sixteen structural T1‐weighted and 9 diffusion‐weighted MR images from 12 PHTS patients and neurotypical controls were used for structural and high‐angular resolution diffusion MRI (HARDI) tractography analyses. Mega‐corpus callosum was observed in 75%, polymicrogyria in 33%, periventricular white matter lesions in 83%, and heterotopia in 17% of the PHTS participants. While gyrification index and hemispheric cortical thickness showed no significant differences between the two groups, significantly increased global and regional brain volumes, and regionally thicker cortices in PHTS participants were observed. HARDI tractography showed increased volume and length of callosal pathways, increased volume of the arcuate fasciculi (AF), and increased length of the bilateral inferior longitudinal fasciculi (ILF), bilateral inferior fronto‐occipital fasciculi (IFOF), and bilateral uncinate fasciculus. A decrease in fractional anisotropy and an increased in apparent diffusion coefficient values of the AF, left ILF, and left IFOF in PHTS.     

Psychometric properties of the Adolescent Sleep Hygiene Scale

This study evaluated the psychometric properties of the Adolescent Sleep Hygiene Scale (ASHS), a self‐report measure assessing sleep practices theoretically important for optimal sleep. Data were collected on a community sample of 514 adolescents (16–19; 17.7 ± 0.4 years; 50% female) participating in the late adolescent examination of a longitudinal study on sleep and health. Sleep hygiene and daytime sleepiness were obtained from adolescent reports, behavior from caretaker reports, and sleep‐wake estimation on weekdays from wrist actigraphy. Confirmatory factor analysis indicated the empirical and conceptually based factor structure were similar for six of the eight proposed sleep hygiene domains. Internal consistency of the revised scale (ASHSr) was α = 0.84; subscale alphas were: physiological: α = 0.60; behavioural arousal: α = 0.62; cognitive/emotional: α = 0.81; sleep environment: α = 0.61; sleep stability: α = 0.68; daytime sleep: α = 0.78. Sleep hygiene scores were associated positively with sleep duration (r = 0.16) and sleep efficiency (r = 0.12) and negatively with daytime sleepiness (r = ?0.26). Results of extreme‐groups analyses comparing ASHSr scores in the lowest and highest quintile provided further evidence for concurrent validity. Correlations between sleep hygiene scores and caretaker reports of school competence, internalizing and externalizing behaviours provided support for convergent validity. These findings indicate that the ASHSr has satisfactory psychometric properties for a research instrument and is a useful research tool for assessing sleep hygiene in adolescents.     

Yield of annual endometrial cancer surveillance in women with PTEN Hamartoma Tumor Syndrome

ObjectiveExpert-opinion based guidelines state that endometrial cancer surveillance (ECS) might be considered for patients with PTEN Hamartoma Tumor Syndrome (PHTS) based on an elevated lifetime risk of endometrial cancer. We aimed to evaluate the yield of ECS by annual transvaginal ultrasound (TVUS) and endometrial biopsy (EMB) in PHTS patients.MethodsPHTS patients who visited our PHTS expert center between August 2012 and September 2020 and opted for annual ECS were included. Data on surveillance visits, diagnostics, reports of abnormal uterine bleeding and pathology results were retrospectively gathered and analyzed.ResultsSurveillance was initiated in 25 women with a total of 93 gynecological surveillance visits during 76 surveillance years. The median age at first visit was 39 years (range 31–60) with a median follow-up duration of 38 months (range 6–96). Hyperplasia with and without atypia was detected six and three times, respectively, in seven (28%) women. The median age at hyperplasia detection was 40 years (range 31–50). In six asymptomatic women hyperplasia was detected during annual surveillance visits, while in one patient hyperplasia with atypia was detected during an additional visit due to abnormal uterine bleeding. In seven out of nine hyperplasias detected with EMB, TVUS beforehand showed no abnormalities. No (interval) carcinomas occurred.ConclusionsECS in women with PHTS enables detection of a substantial number of asymptomatic premalignancies, such as hyperplasia with and without atypia, suggesting that ECS may be beneficial with regard to cancer prevention. The addition of EMB to TVUS likely improves the detection of premalignancies.     

United airways again: high prevalence of rhinosinusitis and nasal polyps in bronchiectasis

Background: Although various relationships between the lower and upper airways have been found, the association of bronchiectasis with chronic rhinosinusitis and nasal polyps has not been thoroughly evaluated. This study was undertaken to examine the association of idiopathic and postinfective bronchiectasis with chronic rhinosinusitis and nasal polyposis. Methods: In a prospective study, 56 patients with idiopathic and 32 with postinfective bronchiectasis were evaluated for chronic rhinosinusitis and nasal polyposis by using EP³OS criteria and assessing: symptoms score, nasal endoscopy, sinonasal and chest CT scan, nasal and lung function and nasal and exhaled NO. Results: Most bronchiectasis patients (77%) satisfied the EP³OS criteria for chronic rhinosinusitis, with anterior (98.5%) and posterior (91%) rhinorrhea and nasal congestion (90%) being the major symptoms. Patients presented maxillary, ethmoidal and ostiomeatal complex occupancy with a total CT score of 8.4 ± 0.4 (0–24). Using endoscopy, nasal polyps with a moderate score of 1.6 ± 0.1 (0–3) were found in 25% of patients. Nasal NO was significantly lower in patients with nasal polyposis (347 ± 62 ppb) than in those without them (683 ± 76 ppb; P < 0.001), and inversely correlated (R = ?0.36; P < 0.01) with the ostiomeatal complex occupancy. In the chest CT scan, patients with chronic rhinosinusitis showed a higher bronchiectasis severity score (7.2 ± 0.5; P < 0.001) than patients without (3.7 ± 0.7). The prevalence of chronic rhinosinusitis, nasal polyps and other outcomes were similar in idiopathic and postinfective bronchiectasis. Conclusions: The frequent association of chronic rhinosinusitis and nasal polyposis with idiopathic and postinfective BQ supports the united airways concept, and it suggests that the two type of bronchiectasis share common etiopathogenic mechanisms.     

Red flags for early recognition of adult patients with PTEN Hamartoma Tumour Syndrome

Patients with PTEN Hamartoma Tumour Syndrome (PHTS) are at increased risk of developing cancer. Many adult PHTS patients are not recognized as such and do not receive the cancer surveillance they need. Our aim was to define phenotypic characteristics that can easily be assessed and manifest by early adulthood, and hence could serve as red flags (i.e. alerting signals) for early recognition of adult patients at high risk of PHTS. Phenotypic characteristics including macrocephaly, multinodular goitre (MNG), and oral features were examined in 81 paediatric and 86 adult PHTS patients by one of two medical experts during yearly surveillance visits at our Dutch PHTS expert centre between 1997 and 2020. MNG was defined as signs of thyroid nodules and/or goitre. Oral features included gingival hypertrophy, high palate (adults only) and oral papillomas. Based on the characteristics’ prevalence in different age groups, combinations of phenotypic characteristics were defined and evaluated on their potential to recognize individuals with PHTS. Macrocephaly was present in 100% of paediatric and 67% of adult patients. The prevalence of MNG was ∼50% in paediatric and gradually increased to >90% in adult patients. Similar percentages were observed for any of the oral features. Scoring two out of three of these characteristics yielded a sensitivity of 100% (95%CI 94–100%) in adults. The presence of the combination macrocephaly, MNG, or multiple oral features could serve as a red flag for general practitioners, medical specialists, and dentists to consider further assessment of the diagnosis PHTS in adults. In this way, recognition of adult PHTS patients might be improved and cancer surveillance can be offered timely.     

Genetic basis of neurodevelopmental disorders in 103 Jordanian families

We recruited 103 families from Jordan with neurodevelopmental disorders (NDD) and patterns of inheritance mostly suggestive of autosomal recessive inheritance. In each family, we investigated at least one affected individual using exome sequencing and an in-house diagnostic variant interpretation pipeline including a search for copy number variation. This approach led us to identify the likely molecular defect in established disease genes in 37 families. We could identify 25 pathogenic nonsense and 11 missense variants as well as 3 pathogenic copy number variants and 1 repeat expansion. Notably, 11 of the disease-causal variants occurred de novo. In addition, we prioritized a homozygous frameshift variant in PUS3 in two sisters with intellectual disability. To our knowledge, PUS3 has been postulated only recently as a candidate disease gene for intellectual disability in a single family with three affected siblings. Our findings provide additional evidence to establish loss of PUS3 function as a cause of intellectual disability.     

Combining exome/genome sequencing with data repository analysis reveals novel gene–disease associations for a wide range of genetic disorders

PurposeWithin this study, we aimed to discover novel gene–disease associations in patients with no genetic diagnosis after exome/genome sequencing (ES/GS).MethodsWe followed two approaches: (1) a patient-centered approach, which after routine diagnostic analysis systematically interrogates variants in genes not yet associated to human diseases; and (2) a gene variant centered approach. For the latter, we focused on de novo variants in patients that presented with neurodevelopmental delay (NDD) and/or intellectual disability (ID), which are the most common reasons for genetic testing referrals. Gene–disease association was assessed using our data repository that combines ES/GS data and Human Phenotype Ontology terms from over 33,000 patients.ResultsWe propose six novel gene–disease associations based on 38 patients with variants in the BLOC1S1, IPO8, MMP15, PLK1, RAP1GDS1, and ZNF699 genes. Furthermore, our results support causality of 31 additional candidate genes that had little published evidence and no registered OMIM phenotype (56 patients). The phenotypes included syndromic/nonsyndromic NDD/ID, oral–facial–digital syndrome, cardiomyopathies, malformation syndrome, short stature, skeletal dysplasia, and ciliary dyskinesia.ConclusionOur results demonstrate the value of data repositories which combine clinical and genetic data for discovering and confirming gene–disease associations. Genetic laboratories should be encouraged to pursue such analyses for the benefit of undiagnosed patients and their families.