Role of CAMK2D in neurodevelopment and associated conditions.

The calcium/calmodulin-dependent protein kinase type 2 (CAMK2) family consists of four different isozymes, encoded by four different genes-CAMK2A, CAMK2B, CAMK2G, and CAMK2D-of which the first three have been associated recently with neurodevelopmental disorders. CAMK2D is one of the major CAMK2 proteins expressed in the heart and has been associated with cardiac anomalies. Although this CAMK2 isoform is also known to be one of the major CAMK2 subtypes expressed during early brain development, it has never been linked with neurodevelopmental disorders until now. Here we show that CAMK2D plays an important role in neurodevelopment not only in mice but also in humans. We identified eight individuals harboring heterozygous variants in CAMK2D who display symptoms of intellectual disability, delayed speech, behavioral problems, and dilated cardiomyopathy. The majority of the variants tested lead to a gain of function (GoF), which appears to cause both neurological problems and dilated cardiomyopathy. In contrast, loss-of-function (LoF) variants appear to induce only neurological symptoms. Together, we describe a cohort of individuals with neurodevelopmental disorders and cardiac anomalies, harboring pathogenic variants in CAMK2D, confirming an important role for the CAMK2D isozyme in both heart and brain function.

POLR1A variants underlie phenotypic heterogeneity in craniofacial, neural, and cardiac anomalies.

Heterozygous pathogenic variants in POLR1A, which encodes the largest subunit of RNA Polymerase I, were previously identified as the cause of acrofacial dysostosis, Cincinnati-type. The predominant phenotypes observed in the cohort of 3 individuals were craniofacial anomalies reminiscent of Treacher Collins syndrome. We subsequently identified 17 additional individuals with 12 unique heterozygous variants in POLR1A and observed numerous additional phenotypes including neurodevelopmental abnormalities and structural cardiac defects, in combination with highly prevalent craniofacial anomalies and variable limb defects. To understand the pathogenesis of this pleiotropy, we modeled an allelic series of POLR1A variants in vitro and in vivo. In vitro assessments demonstrate variable effects of individual pathogenic variants on ribosomal RNA synthesis and nucleolar morphology, which supports the possibility of variant-specific phenotypic effects in affected individuals. To further explore variant-specific effects in vivo, we used CRISPR-Cas9 gene editing to recapitulate two human variants in mice. Additionally, spatiotemporal requirements for Polr1a in developmental lineages contributing to congenital anomalies in affected individuals were examined via conditional mutagenesis in neural crest cells (face and heart), the second heart field (cardiac outflow tract and right ventricle), and forebrain precursors in mice. Consistent with its ubiquitous role in the essential function of ribosome biogenesis, we observed that loss of Polr1a in any of these lineages causes cell-autonomous apoptosis resulting in embryonic malformations. Altogether, our work greatly expands the phenotype of human POLR1A-related disorders and demonstrates variant-specific effects that provide insights into the underlying pathogenesis of ribosomopathies.

Expanding the phenotype of neurofibromatosis type 1 microdeletion syndrome.

Neurofibromatosis type 1 (NF-1) microdeletion syndrome accounts for 5 to 11% of individuals with NF-1. The aim of our study was to characterize a large cohort of individuals with NF-1 microdeletion syndrome and expand its natural history. We conducted a retrospective chart review from 1994 to 2024 of individuals with NF-1 microdeletion syndrome followed at two large Neurofibromatosis Clinics. This cohort consists of 57 individuals with NF-1 microdeletion syndrome (28 type-1, 4 type-2, 2 type-3, 9 atypical deletions, and 14 indeterminate). We note 38/56 (67.9%) with describable facial features, 25/57 (43.8%) with plexiform neurofibromas, and 3/57 (5.2%) with malignant peripheral nerve sheath tumors within the observed period. The most reported neurodevelopmental manifestations from school-age or older individuals included 39/49 (79.6%) with developmental delays, 35/49 (71.4%) with expressive and/or receptive speech delays, 33/41 (80.5%) with learning difficulties, and 23/42 (54.8%) with attention-deficit/hyperactivity disorder. Full-scale IQ testing data was available for 22 individuals (range: 50-96). Of the 21 adults in this cohort, 14/21 (66.7%) graduated from high school, and 4/21 (19.0%) had some college experience. Many individuals received academic support (i.e., special education, individual education plan). In this cohort, neurocognitive outcomes in adults varied more than typically reported in the literature.

A human importin-ß-related disorder: Syndromic thoracic aortic aneurysm caused by bi-allelic loss-of-function variants in IPO8.

Importin 8, encoded by IPO8, is a ubiquitously expressed member of the importin-ß protein family that translocates cargo molecules such as proteins, RNAs, and ribonucleoprotein complexes into the nucleus in a RanGTP-dependent manner. Current knowledge of the cargoes of importin 8 is limited, but TGF-ß signaling components such as SMAD1-4 have been suggested to be among them. Here, we report that bi-allelic loss-of-function variants in IPO8 cause a syndromic form of thoracic aortic aneurysm (TAA) with clinical overlap with Loeys-Dietz and Shprintzen-Goldberg syndromes. Seven individuals from six unrelated families showed a consistent phenotype with early-onset TAA, motor developmental delay, connective tissue findings, and craniofacial dysmorphic features. A C57BL/6N Ipo8 knockout mouse model recapitulates TAA development from 8-12 weeks onward in both sexes but most prominently shows ascending aorta dilatation with a propensity for dissection in males. Compliance assays suggest augmented passive stiffness of the ascending aorta in male Ipo8-/- mice throughout life. Immunohistological investigation of mutant aortic walls reveals elastic fiber disorganization and fragmentation along with a signature of increased TGF-ß signaling, as evidenced by nuclear pSmad2 accumulation. RT-qPCR assays of the aortic wall in male Ipo8-/- mice demonstrate decreased Smad6/7 and increased Mmp2 and Ccn2 (Ctgf) expression, reinforcing a role for dysregulation of the TGF-ß signaling pathway in TAA development. Because importin 8 is the most downstream TGF-ß-related effector implicated in TAA pathogenesis so far, it offers opportunities for future mechanistic studies and represents a candidate drug target for TAA.

Novel insights into the phenotypic spectrum and pathogenesis of Hardikar syndrome.

PURPOSE: Hardikar syndrome (HS, MIM #301068) is a female-specific multiple congenital anomaly syndrome characterized by retinopathy, orofacial clefting, aortic coarctation, biliary dysgenesis, genitourinary malformations, and intestinal malrotation. We previously showed that heterozygous nonsense and frameshift variants in MED12 cause HS. The phenotypic spectrum of disease and the mechanism by which MED12 variants cause disease is unknown. We aim to expand the phenotypic and molecular landscape of HS and elucidate the mechanism by which MED12 variants cause disease. METHODS: We clinically assembled and molecularly characterized a cohort of 11 previously unreported individuals with HS. Additionally, we studied the effect of MED12 deficiency on ciliary biology, hedgehog, and yes-associated protein (YAP) signaling; pathways implicated in diseases with phenotypic overlap with HS. RESULTS: We report novel phenotypes associated with HS, including cardiomyopathy, arrhythmia, and vascular anomalies, and expand the molecular landscape of HS to include splice site variants. We additionally demonstrate that MED12 deficiency causes decreased cell ciliation, and impairs hedgehog and YAP signaling. CONCLUSION: Our data support updating HS standard-of-care to include regular cardiac imaging, arrhythmia screening, and vascular imaging. We further propose that dysregulation of ciliogenesis and YAP and hedgehog signaling contributes to the pathogenesis of HS.

Prenatal and infantile diagnosis of craniosynostosis in individuals with RASopathies.

Fetuses with RASopathies can have a wide variety of anomalies including increased nuchal translucency, hydrops fetalis, and structural anomalies (typically cardiac and renal). There are few reports that describe prenatal-onset craniosynostosis in association with a RASopathy diagnosis. We present clinical and molecular characteristics of five individuals with RASopathy and craniosynostosis. Two were diagnosed with craniosynostosis prenatally, 1 was diagnosed as a neonate, and 2 had evidence of craniosynostosis noted as neonates without formal diagnosis until later. Two of these individuals have Noonan syndrome (PTPN11 and KRAS variants) and three individuals have Cardiofaciocutaneous syndrome (KRAS variants). Three individuals had single suture synostosis and two had multiple suture involvement. The most common sutures involved were sagittal (n = 3), followed by coronal (n = 3), and lambdoid (n = 2) sutures. This case series confirms craniosynostosis as one of the prenatal findings in individuals with RASopathies and emphasizes the importance of considering a RASopathy diagnosis in fetuses with multiple anomalies in combination with craniosynostosis.

Phenotypes and genotypes in a cohort of children with single-ventricle CHD.

OBJECTIVE: CHD is known to be associated with increased risk for neurodevelopmental disorders. The combination of CHD with neurodevelopmental disorders and/or extra-cardiac anomalies increases the chance for an underlying genetic diagnosis. Over the last 15 years, there has been a dramatic increase in the use of broad-scale genetic testing. We sought to determine if neurodevelopmental disorders in children with single-ventricle CHD born prior to the genetic testing revolution are associated with genetic diagnosis. METHODS: We identified 74 5-12-year-old patients with single-ventricle CHD post-Fontan procedure. We retrospectively evaluated genetic testing performed and neurodevelopmental status of these patients. RESULTS: In this cohort, there was an overall higher rate of neurodevelopmental disorders (80%) compared to the literature (50%). More of the younger (5-7-year-old) patients were seen by genetic counsellors compared to the older (8-12-year-old) cohort (46% versus 19% p value = 0.01). In the younger cohort, the average age of initial consultation was 7.7 days compared to 251 days in the older cohort. The overall rate of achieving a molecular diagnosis was 12% and 8% in the younger and older cohorts, respectively; however, the vast majority of did not have broad genetic testing. CONCLUSION: The minority of patients in our cohort achieved a genetic diagnosis. Given a large increase in the number of genes associated with monogenic CHD and neurodevelopmental disorders in the last decade, comprehensive testing and consultation with clinical genetics should be considered in this age range, since current testing standards did not exist during their infancy.

Further expansion and confirmation of phenotype in rare loss of YWHAE gene distinct from Miller-Dieker syndrome.

Deletion of 17p13.3 has varying degrees of severity on brain development based on precise location and size of the deletion. The most severe phenotype is Miller-Dieker syndrome (MDS) which is characterized by lissencephaly, dysmorphic facial features, growth failure, developmental disability, and often early death. Haploinsufficiency of PAFAH1B1 is responsible for the characteristic lissencephaly in MDS. The precise role of YWHAE haploinsufficiency in MDS is unclear. Case reports are beginning to elucidate the phenotypes of individuals with 17p13.3 deletions that have deletion of YWHAE but do not include deletion of PAFAH1B1. Through our clinical genetics practice, we identified four individuals with 17p13.3 deletion that include YWHAE but not PAFAH1B1. These patients have a similar phenotype of dysmorphic facial features, developmental delay, and leukoencephalopathy. In a review of the literature, we identified 19 patients with 17p13.3 microdeletion sparing PAFAH1B1 but deleting YWHAE. Haploinsufficiency of YWHAE is associated with brain abnormalities including cystic changes. These individuals have high frequency of epilepsy, intellectual disability, and dysmorphic facial features including prominent forehead, epicanthal folds, and broad nasal root. We conclude that deletion of 17p13.3 excluding PAFAH1B1 but including YWHAE is associated with a consistent phenotype and should be considered a distinct condition from MDS.

Consolidation of the clinical and genetic definition of a SOX4-related neurodevelopmental syndrome.

BACKGROUND: A neurodevelopmental syndrome was recently reported in four patients with SOX4 heterozygous missense variants in the high-mobility-group (HMG) DNA-binding domain. The present study aimed to consolidate clinical and genetic knowledge of this syndrome. METHODS: We newly identified 17 patients with SOX4 variants, predicted variant pathogenicity using in silico tests and in vitro functional assays and analysed the patients' phenotypes. RESULTS: All variants were novel, distinct and heterozygous. Seven HMG-domain missense and five stop-gain variants were classified as pathogenic or likely pathogenic variant (L/PV) as they precluded SOX4 transcriptional activity in vitro. Five HMG-domain and non-HMG-domain missense variants were classified as of uncertain significance (VUS) due to negative results from functional tests. When known, inheritance was de novo or from a mosaic unaffected or non-mosaic affected parent for patients with L/PV, and from a non-mosaic asymptomatic or affected parent for patients with VUS. All patients had neurodevelopmental, neurological and dysmorphic features, and at least one cardiovascular, ophthalmological, musculoskeletal or other somatic anomaly. Patients with L/PV were overall more affected than patients with VUS. They resembled patients with other neurodevelopmental diseases, including the SOX11-related and Coffin-Siris (CSS) syndromes, but lacked the most specific features of CSS. CONCLUSION: These findings consolidate evidence of a fairly non-specific neurodevelopmental syndrome due to SOX4 haploinsufficiency in neurogenesis and multiple other developmental processes.

Central nervous system involvement in individuals with RASopathies.

Central nervous system (CNS) anomalies are common in individuals with RASopathies. While certain findings, including relative or absolute macrocephaly, are typical for most RASopathies, other findings are more common in certain conditions, with rare low-grade gliomas in Noonan syndrome (NS); Chiari 1 malformation and tethered cord in Costello syndrome (CS); and variable structural anomalies including heterotopia and hydrocephalus in cardio-facio-cutaneous syndrome (CFC). We performed a literature review and present aggregate data on the common and uncommon CNS manifestations in individuals with RASopathies. A gene-based approach to defining risk for specific abnormalities may be considered. However, limited information on the CNS findings of rare RASopathies, such as autosomal recessive LZTR1-related NS or PPP1CB-related NS with loose anagen hair (NSLH), is currently available. Thus, consideration of the RASopathies as a group of distinct syndromic conditions with shared underlying causes and overlapping clinical presentations remains relevant, and individuals with a RASopathy are at risk for many findings seen in these conditions.

Using deep learning and electronic health records to detect Noonan syndrome in pediatric patients.

PURPOSE: The variable expressivity and multisystem features of Noonan syndrome (NS) make it difficult for patients to obtain a timely diagnosis. Genetic testing can confirm a diagnosis, but underdiagnosis is prevalent owing to a lack of recognition and referral for testing. Our study investigated the utility of using electronic health records (EHRs) to identify patients at high risk of NS. METHODS: Using diagnosis texts extracted from Cincinnati Children's Hospital's EHR database, we constructed deep learning models from 162 NS cases and 16,200 putative controls. Performance was evaluated on 2 independent test sets, one containing patients with NS who were previously diagnosed and the other containing patients with undiagnosed NS. RESULTS: Our novel method performed significantly better than the previous method, with the convolutional neural network model achieving the highest area under the precision-recall curve in both test sets (diagnosed: 0.43, undiagnosed: 0.16). CONCLUSION: The results suggested the validity of using text-based deep learning methods to analyze EHR and showed the value of this approach as a potential tool to identify patients with features of rare diseases. Given the paucity of medical geneticists, this has the potential to reduce disease underdiagnosis by prioritizing patients who will benefit most from a genetics referral.

Craniosynostosis is a feature of Costello syndrome.

Costello syndrome (CS) is an autosomal dominant disorder caused by pathogenic variants in HRAS. Craniosynostosis is a known feature of other RASopathies (Noonan and cardiofaciocutaneous syndromes) but not CS. We describe four individuals with CS and craniosynostosis and present a summary of all previously reported individuals with craniosynostosis and RASopathy.

Genetic and phenotypic heterogeneity in KIAA0753-related ciliopathies.

Primary ciliopathies are heterogenous disorders resulting from perturbations in primary cilia form and/or function. Primary cilia are cellular organelles which mediate key signaling pathways during development, such as the sonic hedgehog (SHH) pathway which is required for neuroepithelium and central nervous system development. Joubert syndrome is a primary ciliopathy characterized by cerebellar/brain stem malformation, hypotonia, and developmental delays. At least 35 genes are associated with Joubert syndrome, including the gene KIAA0753, which is part of a complex required for primary ciliogenesis. The phenotypic spectrum associated with biallelic pathogenic variants in KIAA0753 is broad and not well-characterized. We describe four individuals with biallelic pathogenic KIAA0753 variants, including five novel variants. We report in vitro results assessing the function of each variant indicating that mutant proteins are not fully competent to promote primary ciliogenesis. Ablation of KIAA0753 in vitro blocks primary ciliogenesis and SHH pathway activity. Correspondingly, KIAA0753 patient fibroblasts have a deficit in primary ciliation and improper SHH and WNT signaling, with a particularly blunted response to SHH pathway stimulation. Our work expands the phenotypic spectrum of KIAA0753 ciliopathies and demonstrates the utility of patient-focused functional assays for proving causality of genetic variants.

Robin sequence without cleft palate: Genetic diagnoses and management implications.

Robin sequence (RS), the triad of micrognathia, glossoptosis, and airway obstruction, is a major cause of respiratory distress and feeding difficulties in neonates. Robin sequence can be associated with other medical or developmental comorbidities in ~50% of cases ("syndromic" RS). As well, RS is variably associated with cleft palate (CP). Previous studies have not investigated differences in clinical characteristics of children with RS based on presence or absence of CP. We retrospectively reviewed 175 children with RS and compared genetic diagnoses, medical and developmental comorbidities, severity of airway obstruction, and feeding outcomes between those with and without CP. Strikingly, 45 of 45 (100%) children with RS without CP were classified as syndromic due to presence of comorbidities unrelated to RS, while 83 of 130 (64%) children with RS with CP were classified as syndromic. Among 128 children with syndromic RS, there were no differences in severity of airway obstruction, surgical intervention rate or type, or feeding outcome at 12 months based on CP status. Our findings support the conclusion that the pathogenesis of RS without CP is distinct from RS with CP and more likely to cause additional medical or developmental problems. Alternatively, children with RS without CP and without additional anomalies present may be under recognized.

Managing organic dairy herd health: Current roles and possible future roles for veterinarians with organic dairy clientele.

This study aimed to understand the veterinary-client relationship and perspectives in organic dairy production systems. Twenty-three organic dairy producers and 12 veterinarians were interviewed using semi-structured, one-on-one interviews. Consultation with local veterinarians was typically infrequent, as there was greater reliance on other producers and organic industry professionals for advice on dairy herd health management, perhaps due to a shared focus on organic farming principles. Organic producers generally consulted local veterinarians most frequently to develop vaccine protocols, address animal health emergencies, and gain reproductive services. Common reasons organic producers cited for not regularly consulting a local veterinarian included the cost of veterinary services and a perception that local veterinarians have limited experience with organic systems and products. Some producers also expressed the idea that infrequent veterinarian usage is indicative of a healthy herd. Meanwhile, local veterinarians reported that organic dairy producers often delayed consulting them about individual cases until animal health problems were severe. Local veterinarians also identified challenges in servicing organic herds, such as the lack of standardized regulations between different organic certifiers and limited safety and efficacy data for many herd health products used by organic producers. In addition, their formal training generally did not include organic herd health strategies. Organic dairy clients were typically a small fraction of the overall workload for local veterinarians, which precluded their ability to accumulate experience. In contrast, a handful of specialized veterinarians in the organic milk processing industry work more frequently with organic producers and have published most of the available resource materials on organic dairy herd health. Veterinary-client partnerships could be improved through more open communication and discussion of the challenges identified in this study and through participatory research and outreach engagement that includes local veterinarians, organic certifiers, organic industry veterinarians, and producers.

Mandibulofacial dysostosis with microcephaly: An expansion of the phenotype via parental survey.

Mandibulofacial dysostosis with microcephaly (MFDM) is due to haploinsufficiency of spliceosomal GTPase EFTUD2. Features include microcephaly, craniofacial dysmorphology, developmental disability, and other anomalies. We surveyed parents of individuals with MFDM to expand knowledge about health, development, and parental concerns. Participants included attendees of the inaugural MFDM family conference in June 2019 and members of the MFDM online group. To explore MFDM variable expressivity, we offered targeted Sanger sequencing for untested parents. Forty-seven parents participated in the survey. 59% of individuals with MFDM were male, with mean age 6.4 years (range 8 months to 49 years). Similar to the literature (n = 123), common features include microcephaly, cleft palate, choanal stenosis, tracheoesophageal fistula, heart problems, and seizures. New information includes airway intervention details, age-based developmental outcomes, rate of vision refractive errors, and lower incidences of prematurity and IUGR. Family concerns focused on development, communication, and increased support. Targeted Sanger sequencing for families of seven individuals demonstrated de novo variants, for a total of 91.9% de novo EFTUD2 variants (n = 34/37). This study reports the largest single cohort of individuals with MFDM, expands phenotypic spectrum and inheritance patterns, improves understanding of developmental outcomes and care needs, and identifies development as the biggest concern for parents.

Organic dairy producer experiences and decisions related to disease prevention and treatment.

Organic dairy producers have distinct perspectives, approaches, challenges, and experiences when managing herd health, but little research has been conducted to develop a deeper understanding of producer decision-making related to disease-prevention and treatment strategies. We used 23 semi-structured interviews with organic dairy producers to better understand their perceived herd health challenges and overall disease-prevention strategies; decision-making and attitudes related to vaccination; and approaches to the treatment of infectious diseases using alternative or conventional antimicrobial therapies. Organic dairy producers reported improvements in overall animal health after they transitioned from a conventional to an organic system. Outdoor access, a balanced forage-based diet, and animal and environmental cleanliness were reported as the predominant disease-prevention measures. Over half of producers vaccinated their animals, and almost all preferred to use vaccines sparingly. Among producers who did not use vaccines, reasons cited were low perceived risk for infectious disease and minor vaccine safety concerns, yet many were not opposed to using vaccines in the future. Non-antimicrobial therapies were viewed as alternative effective treatment strategies for most common infectious diseases. Producers used antimicrobials very rarely and generally reserved them for severe cases when alternative treatments failed. Because US organic standards prohibit selling milk from cows that have ever been treated with antimicrobials, producers described the decision to use antimicrobials as extremely challenging and involved balancing considerations of economics, convenience, and animal welfare. This research fosters a better understanding of organic dairy producers' disease-prevention and treatment strategies and could be used by veterinarians and other animal health specialists to facilitate services for organic clients.

Comparison of Evolution of Aortic Root Dilation and Ghent Criteria in Preadolescents and Adolescents with and without Marfan Syndrome.

OBJECTIVE: To determine whether the Ghent Criteria (2010) can be reliably used in evaluating preadolescents and adolescents for Marfan syndrome by comparing aortic growth, systemic scores, and anthropometric features in individuals with and without Marfan syndrome. STUDY DESIGN: A retrospective chart review was completed for patients less than 15 years of age referred for Marfan syndrome. Comparisons were made between the first and last visit. Paired t tests were used to compare Ghent systemic scores. Wilcoxon rank-sum test were used to compare age, aortic root z scores, height z scores, and body mass index z scores. Recursive partitioning was used to identify combinations of factors to distinguish Marfan syndrome. RESULTS: In total, 53 individuals met inclusion criteria (29 Marfan syndrome and 24 non-Marfan syndrome). Ghent systemic score increased in the Marfan syndrome group and declined in the non-Marfan syndrome. The non-Marfan syndrome group did not develop progressive aortic root dilation with age. Individuals with Marfan syndrome had higher median height z scores than non-Marfan syndrome, with no difference in median body mass index z score between groups. A combination of aortic root z score above 0.95 and Ghent systemic score above 3 was highly indicative of a Marfan syndrome diagnosis in children less than 15 years of age. CONCLUSION: The Ghent criteria (2010) can be used to reliably exclude a diagnosis of Marfan syndrome in individuals less than 15 years of age. Genetic testing should be used as an aide in confirming or excluding the diagnosis of Marfan syndrome in individuals with an aortic root z score above 0.95 in combination with a Ghent systemic score above 3 at initial visit.

A multi-institutional experience in vascular Ehlers-Danlos syndrome diagnosis.

OBJECTIVE: Vascular Ehlers-Danlos syndrome (vEDS) is a rare disorder and 1 of 13 types of EDS. The syndrome results in aortic and arterial aneurysms and dissections at a young age. Diagnosis is confirmed with molecular testing via skin biopsy or genetic testing for COL3A1 pathogenic variants. We describe a multi-institutional experience in the diagnosis of vEDS from 2000 to 2015. METHODS: This is a multi-institutional cross-sectional retrospective study of individuals with vEDS. The institutions were recruited through the Vascular Low Frequency Disease Consortium. Individuals were identified using the International Classification of Diseases-9 and 10-CM codes for EDS (756.83 and Q79.6). A review of records was then performed to select individuals with vEDS. Data abstraction included demographics, family history, clinical features, major and minor diagnostic criteria, and molecular testing results. Individuals were classified into two cohorts and then compared: those with pathogenic COL3A1 variants and those diagnosed by clinical criteria alone without molecular confirmation. RESULTS: Eleven institutions identified 173 individuals (35.3% male, 56.6% Caucasian) with vEDS. Of those, 11 (9.8%) had nonpathogenic alterations in COL3A1 and were excluded from the analysis. Among the remaining individuals, 86 (47.7% male, 68% Caucasian, 48.8% positive family history) had pathogenic COL3A1 variants and 76 (19.7% male, 19.7% Caucasian, 43.4% positive family history) were diagnosed by clinical criteria alone without molecular confirmation. Compared with the cohort with pathogenic COL3A1 variants, the clinical diagnosis only cohort had a higher number of females (80.3% vs 52.3%; P < .001), mitral valve prolapse (10.5% vs 1.2%; P = .009), and joint hypermobility (68.4% vs 40.7%; P < .001). Additionally, they had a lower frequency of easy bruising (23.7% vs 64%; P < .001), thin translucent skin (17.1% vs 48.8%; P < .001), intestinal perforation (3.9% vs 16.3%; P = .01), spontaneous pneumothorax/hemothorax (3.9% vs 14%, P.03), and arterial rupture (9.2% vs 17.4%; P = .13). There were no differences in mortality or age of mortality between the two cohorts. CONCLUSIONS: This study highlights the importance of confirming vEDS diagnosis by testing for pathogenic COL3A1 variants rather than relying on clinical diagnostic criteria alone given the high degree of overlap with other forms genetically triggered arteriopathies. Because not all COL3A1 variants are pathogenic, the interpretation of the genetic testing results by an individual trained in variant assessment is essential to confirm the diagnosis. An accurate diagnosis is critical and has serious implications for lifelong screening and treatment strategies for the affected individual and family members.

Medically actionable comorbidities in adults with Costello syndrome.

Costello syndrome (CS) is an autosomal-dominant condition caused by activating missense mutations in HRAS. There is little literature describing health concerns specific to adults with CS. Parents of individuals with CS need to know what to anticipate as their children age. We surveyed a group of 20 adults and older adolescents with CS regarding their medical concerns and lifestyle characteristics. We identified several previously undescribed actionable medical concerns in adults with CS. First, the high prevalence of anxiety in this cohort indicates that screening for anxiety is warranted since this is a treatable condition that can have a significant impact on quality of life. Second, adults with CS should be monitored for progressive contractures or other problems that could decrease mobility. This is especially important in a population that seems to have increased risk for osteopenia. Finally, the lack of cancer diagnoses in adulthood is of interest, although the cohort is too small to draw definitive conclusions about cancer risk in adults with CS. Ongoing follow-up of the current cohort of adults with CS is necessary to delineate progressive medical and physical problems, which is essential for providing targeted management recommendations and anticipatory guidance to families.