The importance of patient-specific resources for families dealing with prenatal rare diseases.

Rare diseases (RDs) are defined as diseases that affect a low number of the population. Prenatal diagnoses of RDs can add a lot of unique stress for parents. For example, parents who have prenatal diagnoses experience not only grief of expectation, but are forced to become patient advocates with incomplete information as their child is not yet born, and in many cases parents experience a lot of uncertainty. This typically involves seeking support groups and finding pre- and postnatal specialists all which come with mental and financial cost. Here we discuss the importance of targeted patient resources for parents to help alleviate some of their stress. Patient advocacy organizations can be incredibly useful for parents to navigate the complex healthcare system and help mitigate feelings of isolation, especially when parents can talk to others in a similar situation. We collaborated with a patient organization to create a prenatal parent support guide to address how parental needs such as mental well-being and practicing self-care can be met. We hope that resources such as these can help empower those with a pregnancy affected with a RD diagnosis.

Amniocentesis in pregnancies at or beyond 24 weeks: an international multicenter study.

BACKGROUND: Amniocentesis for genetic diagnosis is most commonly done between 15 and 22 weeks of gestation but can be performed at later gestational ages. The safety and genetic diagnostic accuracy of amniocentesis have been well-established through numerous large-scale multicenter studies for procedures before 24 weeks, but comprehensive data on late amniocentesis remain sparse. OBJECTIVE: To evaluate the indications, diagnostic yield, safety, and maternal and fetal outcomes associated with amniocentesis performed at or beyond 24 weeks of gestation. STUDY DESIGN: We conducted an international multicenter retrospective cohort study examining pregnant individuals who underwent amniocentesis for prenatal diagnostic testing at gestational ages between 24w0d and 36w6d. The study, spanning from 2011 to 2022, involved 9 referral centers. We included singleton or twin pregnancies with documented outcomes, excluding cases where other invasive procedures were performed during pregnancy or if amniocentesis was conducted for obstetric indications. We analyzed indications for late amniocentesis, types of genetic tests performed, their results, and the diagnostic yield, along with pregnancy outcomes and postprocedure complications. RESULTS: Of the 752 pregnant individuals included in our study, late amniocentesis was primarily performed for the prenatal diagnosis of structural anomalies (91.6%), followed by suspected fetal infection (2.3%) and high-risk findings from cell-free DNA screening (1.9%). The median gestational age at the time of the procedure was 28w5d, and 98.3% of pregnant individuals received results of genetic testing before birth or pregnancy termination. The diagnostic yield was 22.9%, and a diagnosis was made 2.4 times more often for fetuses with anomalies in multiple organ systems (36.4%) compared to those with anomalies in a single organ system (15.3%). Additionally, the diagnostic yield varied depending on the specific organ system involved, with the highest yield for musculoskeletal anomalies (36.7%) and hydrops fetalis (36.4%) when a single organ system or entity was affected. The most prevalent genetic diagnoses were aneuploidies (46.8%), followed by copy number variants (26.3%) and monogenic disorders (22.2%). The median gestational age at delivery was 38w3d, with an average of 59 days between the procedure and delivery date. The overall complication rate within 2 weeks postprocedure was 1.2%. We found no significant difference in the rate of preterm delivery between pregnant individuals undergoing amniocentesis between 24 and 28 weeks and those between 28 and 32 weeks, reinforcing the procedure's safety across these gestational periods. CONCLUSION: Late amniocentesis, at or after 24 weeks of gestation, especially for pregnancies complicated by multiple congenital anomalies, has a high diagnostic yield and a low complication rate, underscoring its clinical utility. It provides pregnant individuals and their providers with a comprehensive diagnostic evaluation and results before delivery, enabling informed counseling and optimized perinatal and neonatal care planning.

The Reliability of Ultrasound Markers in Identifying Fetuses With a Life-Limiting Skeletal Dysplasia.

OBJECTIVE: To determine the diagnostic performance of ultrasound markers associated with life-limiting fetal skeletal dysplasia in a fortified cohort. METHODS: Retrospective review from 2013 to 2023 of pregnancies with suspected fetal skeletal dysplasia. Ultrasound evaluation included measurements predictive of a life-limiting dysplasia: thoracic circumference/abdominal circumference (TC/AC) < 0.6, femur length/abdominal circumference (FL/AC) < 0.16, and thoracic circumference (TC) < 2.5th percentile. Demographics, ultrasound findings, genetic testing, and fetal/neonatal outcome were reviewed. RESULTS: Of 96 fetuses with complete outcome data, 47 (49%) had a non-life-limiting dysplasia and 49 (51%) had a life-limiting dysplasia. 22 (23%) had no life-limiting markers, 42 (44%) had one, 27 (28%) had two, and 5 (5%) had three. FL/AC < 0.16 and TC < 2.5th percentile were associated with life-limiting dysplasia (p < 0.001; p < 0.001), while TC/AC < 0.6 was rare and did not reach statistical significance (p = 0.056). The positive predictive value (PPV) for predicting life-limiting dysplasia increased from 50% to 78% to 100% with one, two, or three markers. The PPV of the two life-limiting markers was significantly higher in those diagnosed at < versus ≥ 28 weeks (90% vs. 43%, p = 0.02) but the analysis was limited by small numbers in the ≥ 28 weeks cohort. The negative predictive value of no life-limiting markers was 91%. CONCLUSIONS: In our cohort, the presence of two life-limiting ultrasound markers prior to 28 weeks was highly suggestive of a life-limiting dysplasia, whereas the absence of life-limiting markers was strongly associated with a non-life-limiting dysplasia throughout gestation. Nonetheless, individual markers had a poor predictive value of lethality, and a life-limiting diagnosis ≥ 28 weeks is challenging based on ultrasound markers alone. This highlights the importance of integrating thorough sonography, genetic testing, and balanced parental counseling.

Prenatal cardiac findings and 22q11.2 deletion syndrome: Fetal detection and evaluation.

Clinical features of 22q11.2 microdeletion syndrome (22q11.2DS) are highly variable between affected individuals and frequently include a subset of conotruncal and aortic arch anomalies. Many are diagnosed with 22q11.2DS when they present as a fetus, newborn or infant with characteristic cardiac findings and subsequently undergo genetic testing. The presence of an aortic arch anomaly with characteristic intracardiac anomalies increases the likelihood that the patient has 22q11.2 DS, but those with an aortic arch anomaly and normal intracardiac anatomy are also at risk. It is particularly important to identify the fetus at risk for 22q11.2DS in order to prepare the expectant parents and plan postnatal care for optimal outcomes. Fetal anatomy scans now readily identify aortic arch anomalies (aberrant right subclavian artery, right sided aortic arch or double aortic arch) in the three-vessel tracheal view. Given the association of 22q11.2DS with aortic arch anomalies with and without intracardiac defects, this review highlights the importance of recognizing the fetus at risk for 22q11.2 deletion syndrome with an aortic arch anomaly and details current methods for genetic testing. To assist in the prenatal diagnosis of 22q11.2DS, this review summarizes the seminal features of 22q11.2DS, its prenatal presentation and current methods for genetic testing.

Enlarged cavum septum pellucidum and small thymus as markers for 22q11.2 deletion syndrome.

BACKGROUND: Enlarged cavum septum pellucidum (CSP) and hypoplastic thymus are proposed extra-cardiac fetal markers for 22q11.2 deletion syndrome. We sought to determine if they were part of the fetal phenotype of our cohort of fetuses with 22q11.2 deletion syndrome. METHODS: Case-control study of fetuses evaluated from 2016 to 2022. The study group included fetuses with laboratory confirmation of 22q11.2 deletion syndrome. The control group included pregnancies with conotruncal cardiac anomalies with normal microarray as well as structurally normal fetuses with normal microarray. The CSP and thymus were routinely measured during anatomical ultrasound in all patients at their initial visit at 27.1 ± 4.7 weeks. The CSP and thymus measurements were classified as abnormal if they were >95% or <5% for gestational age, respectively. The groups were compared using analysis of variance or Kruskal-Wallis for continuous variables and Fisher's exact test for categorical variables. Logistic regression was performed, and a Receiver Operating Characteristic (ROC) curve was constructed. RESULTS: We identified 47 fetuses with 22q11.2 deletion syndrome and compared them to 47 fetuses with conotruncal anomalies and normal microarray and 47 structurally normal fetuses with normal microarray. 51% (24/47) of fetuses with 22q11.2 deletion syndrome had an enlarged CSP compared to 6% (3/47) of fetuses with a conotruncal anomaly and normal microarray and none of the structurally normal fetuses (p < 0.001). Of the fetuses with 22q11.2 deletion syndrome, 83% (39/47) had a hypoplastic or absent thymus compared to 9% (4/47) of the fetuses with a conotruncal anomaly and normal microarray and none of the structurally normal fetuses (p < 0.001). 87% (41/47) of the fetuses with 22q11.2 deletion syndrome had conotruncal cardiac anomalies. Logistic regression revealed that both enlarged CSP and hypoplastic/absent thymus were associated with 22q11.2 deletion syndrome. The area under the ROC curve for the two markers was 0.94. CONCLUSION: An enlarged CSP and hypoplastic/absent thymus appear to be part of the fetal phenotype of 22q11.2 deletion syndrome. These markers are associated with conotruncal anomalies in the setting of 22q11.2 deletion syndrome but not in normal controls or fetuses with conotruncal defects and normal microarrays.

Updated clinical practice recommendations for managing children with 22q11.2 deletion syndrome.

This review aimed to update the clinical practice guidelines for managing children and adolescents with 22q11.2 deletion syndrome (22q11.2DS). The 22q11.2 Society, the international scientific organization studying chromosome 22q11.2 differences and related conditions, recruited expert clinicians worldwide to revise the original 2011 pediatric clinical practice guidelines in a stepwise process: (1) a systematic literature search (1992-2021), (2) study selection and data extraction by clinical experts from 9 different countries, covering 24 subspecialties, and (3) creation of a draft consensus document based on the literature and expert opinion, which was further shaped by survey results from family support organizations regarding perceived needs. Of 2441 22q11.2DS-relevant publications initially identified, 2344 received full-text reviews, including 1545 meeting criteria for potential relevance to clinical care of children and adolescents. Informed by the available literature, recommendations were formulated. Given evidence base limitations, multidisciplinary recommendations represent consensus statements of good practice for this evolving field. These recommendations provide contemporary guidance for evaluation, surveillance, and management of the many 22q11.2DS-associated physical, cognitive, behavioral, and psychiatric morbidities while addressing important genetic counseling and psychosocial issues.

Genomic sequencing in a cohort of individuals with fibular aplasia, tibial campomelia, and oligosyndactyly (FATCO) syndrome.

Fibular aplasia, tibial campomelia, and oligosyndactyly (FATCO) syndrome (MIM 246570) is a rare disorder characterized by specific skeletal findings (fibular aplasia, shortened or bowed tibia, and oligosyndactyly of the foot and/or hand). Typically, no other anomalies, craniofacial dysmorphism, or developmental delays are associated. Here we report three unrelated individuals with limb anomalies consistent with FATCO syndrome who have been followed clinically for 5 years. Genetic testing of previously reported individuals with FATCO syndrome has not revealed a genetic diagnosis. However, no broader sequencing approaches have been reported. We describe the results of the three individuals with FATCO syndrome from exome and genome sequencing, all of which was nondiagnostic. Our study suggests that FATCO syndrome is not the result of a simple monogenic etiology.

The Genomics of Congenital Diaphragmatic Hernia: A 10-Year Retrospective Review.

OBJECTIVE: To evaluate genetic testing use in infants with congenital diaphragmatic hernia (CDH) over the past decade to better inform future practices and individualize prognostication and management. STUDY DESIGN: A retrospective cohort study was performed of all infants with CDH enrolled in the Pulmonary Hypoplasia Program at Children's Hospital of Philadelphia, born between January 2011 and February 2021. For each infant, demographic information, prenatal and postnatal history, and genetic testing were reviewed. RESULTS: The charts of 411 infants were analyzed. Overall, 22% (n = 89) were complex/syndromic and 78% (n = 322) were isolated/nonsyndromic. Mortality was significantly higher in complex/syndromic infants (P < .001) and in infants with diagnostic genetic testing (P < .001). Microarray was diagnostic in 9% (n = 34/399) and exome sequencing was diagnostic in 38% (n = 15/39). Genetic testing was diagnostic in 57% (n = 51/89) of complex/syndromic infants, but in only 2% of isolated/nonsyndromic infants (n = 8/322). Overall, genetic testing was diagnostic in 14% (n = 56). CONCLUSIONS: The high diagnostic rate in this cohort highlights the utility of comprehensive genetic testing in infants with CDH. However, 43% of complex/syndromic and 98% of isolated/nonsyndromic infants do not have a genetic etiology identified. This finding underscores the need for additional genetic and genomic studies (eg, whole genome, RNA sequencing) to identify novel genes and mutational mechanisms (single genes, regulatory elements, complex traits) that will allow for improved diagnostic rates and ultimately individualized management of infants with CDH.

KIAA1109 Variants Are Associated with a Severe Disorder of Brain Development and Arthrogryposis.

Whole-exome and targeted sequencing of 13 individuals from 10 unrelated families with overlapping clinical manifestations identified loss-of-function and missense variants in KIAA1109 allowing delineation of an autosomal-recessive multi-system syndrome, which we suggest to name Alkuraya-Kucinskas syndrome (MIM 617822). Shared phenotypic features representing the cardinal characteristics of this syndrome combine brain atrophy with clubfoot and arthrogryposis. Affected individuals present with cerebral parenchymal underdevelopment, ranging from major cerebral parenchymal thinning with lissencephalic aspect to moderate parenchymal rarefaction, severe to mild ventriculomegaly, cerebellar hypoplasia with brainstem dysgenesis, and cardiac and ophthalmologic anomalies, such as microphthalmia and cataract. Severe loss-of-function cases were incompatible with life, whereas those individuals with milder missense variants presented with severe global developmental delay, syndactyly of 2nd and 3rd toes, and severe muscle hypotonia resulting in incapacity to stand without support. Consistent with a causative role for KIAA1109 loss-of-function/hypomorphic variants in this syndrome, knockdowns of the zebrafish orthologous gene resulted in embryos with hydrocephaly and abnormally curved notochords and overall body shape, whereas published knockouts of the fruit fly and mouse orthologous genes resulted in lethality or severe neurological defects reminiscent of the probands' features.

'Steep learning curves' to 'Smooth Sailing': A reappraisal of telegenetics amidst the COVID-19 pandemic.

The COVID-19 pandemic has pushed medical providers to trial telemedicine on a scale that lacks precedent. In genetic medicine, nearly overnight genetics providers were asked to transition to telemedicine platforms, irrespective of their previous experience with these modalities. This push to telegenetics prompted a reappraisal of the practice, as genetics providers learned firsthand about the feasibility, benefits, and drawbacks of telegenetics and telesupervision, all of which raise questions about the potential incorporation of these platforms beyond the pandemic. Adding to nascent literature on the transition to telegenetics amidst the COVID-19 pandemic, we aimed to evaluate provider experiences and preferences with respect to telegenetics through qualitative semi-structured interviews with genetics providers. Nineteen providers from seven institutions participated in a semi-structured interview focused on the rapid shift to telegenetics, the benefits and drawbacks of the practice, experiences supervising students on virtual platforms, and providers' preferences. We employed a qualitative methodology so that providers working across diverse subspecialties could expand upon previously reported benefits and drawbacks. Qualitative data revealed the nuanced benefits of telegenetics which included overcoming geographic, spatial, and temporal barriers to care as well as greater involvement of patients' family members in sessions. In addition, the data indicated drawbacks related to additional tasks such as completing paperwork electronically and facilitating the collection of specimens from patients' homes. Interviews with providers from different subspecialties revealed how telegenetics may be uniquely useful for particular subspecialties, patient populations, or clinics for whom the aforementioned barriers are more significant. Providers reported that telesupervision made the provision of feedback to students more cumbersome and identified a number of methods for enriching the telesupervision experience. In keeping with previous research, most genetics providers appraised telegenetics as a valuable addition to patient care (68%, N = 13) and hoped to offer it as an option beyond the pandemic (63%, N = 12).

Loss-of-function of Endothelin receptor type A results in Oro-Oto-Cardiac syndrome.

Craniofacial morphogenesis is regulated in part by signaling from the Endothelin receptor type A (EDNRA). Pathogenic variants in EDNRA signaling pathway components EDNRA, GNAI3, PCLB4, and EDN1 cause Mandibulofacial Dysostosis with Alopecia (MFDA), Auriculocondylar syndrome (ARCND) 1, 2, and 3, respectively. However, cardiovascular development is normal in MFDA and ARCND individuals, unlike Ednra knockout mice. One explanation may be that partial EDNRA signaling remains in MFDA and ARCND, as mice with reduced, but not absent, EDNRA signaling also lack a cardiovascular phenotype. Here we report an individual with craniofacial and cardiovascular malformations mimicking the Ednra -/- mouse phenotype, including a distinctive micrognathia with microstomia and a hypoplastic aortic arch. Exome sequencing found a novel homozygous missense variant in EDNRA (c.1142A>C; p.Q381P). Bioluminescence resonance energy transfer assays revealed that this amino acid substitution in helix 8 of EDNRA prevents recruitment of G proteins to the receptor, abrogating subsequent receptor activation by its ligand, Endothelin-1. This homozygous variant is thus the first reported loss-of-function EDNRA allele, resulting in a syndrome we have named Oro-Oto-Cardiac Syndrome. Further, our results illustrate that EDNRA signaling is required for both normal human craniofacial and cardiovascular development, and that limited EDNRA signaling is likely retained in ARCND and MFDA individuals. This work illustrates a straightforward approach to identifying the functional consequence of novel genetic variants in signaling molecules associated with malformation syndromes.

Further delineation of the phenotypic spectrum of nevus comedonicus syndrome to include congenital pulmonary airway malformation of the lung and aneurysm.

Nevus comedonicus syndrome (NCS) is a rare epidermal nevus syndrome characterized by ocular, skeletal, and central nervous system anomalies. We present a 23-month-old boy with a history of a congenital pulmonary airway malformation (CPAM) of the lung and a congenital cataract who developed progressive linear and curvilinear plaques of dilated follicular openings with keratin plugs (comedones) on parts of his scalp, face, and body consistent with nevus comedonicus. MRI of the brain demonstrated an aneurysm of the right internal carotid artery. Genetic testing identified NEK9 c.1755_1757del (p.Thr586del) at mean allele frequency of 28% in the nevus comedonicus. This same mutation was present in the CPAM tissue. This is the first case of a CPAM in a patient with an epidermal nevus syndrome. This case expands the phenotype of nevus comedonicus syndrome to include CPAM and vascular anomalies.

Genetic counseling for fetal gastrointestinal anomalies.

PURPOSE OF REVIEW: Congenital gastrointestinal anomalies are common findings with relatively established methods of treatment. However, the genetic cause of how these defects occur and how that may impact a child's lifelong care is less established. Genetic testing has improved significantly in recent years, yet reviews documenting prenatal genetic counseling and testing guidelines have not been comprehensively updated. RECENT FINDINGS: Congenital anomalies of the foregut, such as tracheoesophageal fistula carry a high association with genetic disorders, both in isolation and syndromic forms. Duodenal atresia remains highly associated with Trisomy 21 but is not enriched in other genetic conditions. Disorders of the midgut, such as omphalocele often have a genetic cause and may require both cytogenetic and panel testing to obtain a diagnosis. The etiologic basis of hindgut malformations remain largely unknown, though imperforate anus as well as Hirschprung's disease have been associated with many micro deletion syndromes as well as in association with other birth defects as part of larger syndromes. SUMMARY: Prenatal diagnostic genetic testing through amniocentesis or chorionic villus sampling can be offered to every patient who wants to learn genetic information about their fetus. Cytogenetic testing, such as microarray is a first tier test to assess cause for these conditions and can provide meaningful answers. When a gastrointestinal anomaly is identified in association with an additionally affected organ system next-generation sequencing and defect-specific genetic testing panels can be necessary to understand cause as well as prognosis to best prepare families for the medical management that lies ahead.

Expanding the fetal phenotype: Prenatal sonographic findings and perinatal outcomes in a cohort of patients with a confirmed 22q11.2 deletion syndrome.

22q deletion syndrome (22q11.2DS) is most often correlated prenatally with congenital heart disease and or cleft palate. The extracardiac fetal phenotype associated with 22q11.2DS is not well described. We sought to review both the fetal cardiac and extracardiac findings associated with a cohort of cases ascertained prenatally, confirmed or suspected to have 22q11.2DS, born and cared for in one center. A retrospective chart review was performed on a total of 42 cases with confirmed 22q11.2DS to obtain prenatal findings, perinatal outcomes and diagnostic confirmation. The diagnosis was confirmed prenatally in 67% (28/42) and postnatally in 33% (14/42). The majority (81%) were associated with the standard LCR22A-LCR22D deletion. 95% (40/42) of fetuses were prenatally diagnosed with congenital heart disease. Extracardiac findings were noted in 90% (38/42) of cases. Additional findings involved the central nervous system (38%), gastrointestinal (14%), genitourinary (16.6%), pulmonary (7%), skeletal (19%), facial dysmorphism (21%), small/hypoplastic thymus (26%), and polyhydramnios (30%). One patient was diagnosed prenatally with a bilateral cleft lip and cleft palate. No fetus was diagnosed with intrauterine growth restriction. The average gestational age at delivery was 38 weeks and average birth weight was 3,105 grams. Sixty-two percentage were delivered vaginally and there were no fetal demises. A diagnosis of 22q11.2 deletion syndrome should be considered in all cases of prenatally diagnosed congenital heart disease, particularly when it is not isolated. Microarray is warranted in all cases of structural abnormalities diagnosed prenatally. Prenatal diagnosis of 22q11.2 syndrome can be used to counsel expectant parents regarding pregnancy outcome and guide neonatal management.

What is new with 22q? An update from the 22q and You Center at the Children's Hospital of Philadelphia.

22q11.2 deletion syndrome (22q11.2DS) is a disorder caused by recurrent, chromosome-specific, low copy repeat (LCR)-mediated copy-number losses of chromosome 22q11. The Children's Hospital of Philadelphia has been involved in the clinical care of individuals with what is now known as 22q11.2DS since our initial report of the association with DiGeorge syndrome in 1982. We reviewed the medical records on our continuously growing longitudinal cohort of 1,421 patients with molecularly confirmed 22q11.2DS from 1992 to 2018. Most individuals are Caucasian and older than 8 years. The mean age at diagnosis was 3.9 years. The majority of patients (85%) had typical LCR22A-LCR22D deletions, and only 7% of these typical deletions were inherited from a parent harboring the deletion constitutionally. However, 6% of individuals harbored other nested deletions that would not be identified by traditional 22q11.2 FISH, thus requiring an orthogonal technology to diagnose. Major medical problems included immune dysfunction or allergies (77%), palatal abnormalities (67%), congenital heart disease (64%), gastrointestinal difficulties (65%), endocrine dysfunction (>50%), scoliosis (50%), renal anomalies (16%), and airway abnormalities. Median full-scale intelligence quotient was 76, with no significant difference between individuals with and without congenital heart disease or hypocalcemia. Characteristic dysmorphic facial features were present in most individuals, but dermatoglyphic patterns of our cohort are similar to normal controls. This is the largest longitudinal study of patients with 22q11.2DS, helping to further describe the condition and aid in diagnosis and management. Further surveillance will likely elucidate additional clinically relevant findings as they age.

Implementation of trauma-informed care strategies in a comprehensive maternal-fetal care center.

OBJECTIVE: To identify traumatic stress symptoms among expectant parents with a confirmed congenital anomaly and describe the ways in which a maternal-fetal care center, with an embedded multidisciplinary psychosocial support team, provides specific trauma-informed strategies to mitigate psychological distress from the first patient contact throughout prenatal care practice. METHOD: Traumatic stress symptoms in response to the confirmed congenital anomaly were assessed using the Impact of Events Scale-Revised. With Institutional Review Board approval, a total of 4,391 pregnant parents and 3,570 partners were analyzed based on routine universal screening performed in a single maternal-fetal care center. Exploratory, descriptive analyses examined rates of overall traumatic stress symptoms and subscale scores. RESULTS: 28.7% of pregnant parents and 24.2% of expectant partners reported elevated traumatic stress symptoms in response to their confirmed congenital anomaly, with clinically significant risk endorsed among 16.2% and 13.4%, respectively. Symptoms of intrusion and avoidance were most notable among parents. Methods of trauma-informed care provided by the multidisciplinary care team in collaboration with the psychosocial support team to identify, support, and intervene with high-risk parents are described. CONCLUSIONS: Recognizing that expectant parents who receive a prenatal diagnosis of a congenital anomaly are at heightened risk for experiencing traumatic stress symptoms, multidisciplinary care teams should offer trauma-informed strategies and psychosocial support services, including parental mental health screening, psychosocial assessment, and clinical intervention, as part of routine prenatal care to reduce the negative effect of emotional distress in the expectant parents prior to birth. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Expanding Genetic Counselor Roles: A Model for Global Research Development.

PURPOSE: Genetic counselors (GCs) increasingly play key roles in advancing genomic medicine through innovative research. Here, we examine one large cohort of GCs' evolving contributions to the literature, with the goal of facilitating worldwide professional development for GCs through scholarly activities. METHODS: Publications were cataloged by members of the Section of Genetic Counseling (Section), established at the Children's Hospital of Philadelphia and the University of Pennsylvania in 2014, including publication year, journal, impact factor, and author position. Data were organized using the "My Bibliography" tool on the National Center for Biotechnology Information website and a Research Electronic Data Capture database created to initially collect manuscripts published through 30 June 2020. A subsequent survey captured publications through 5 February 2024. RESULTS: An amount of 52 of 120 (43%) GCs shared their curriculum vitae/papers. 992 unique publications were identified from 1986 to 2024. Since 2013, no less than 32 papers were published annually by Section members and no less than 10 GCs contributed to publications yearly. Impact factors typically averaged >5.0 per year. Areas of foci diversified considerably since 2015. CONCLUSIONS: Here, we establish that GCs indeed contribute to scholarly work as evidenced by the number of publications alone. The establishment of an academic home may have contributed, given publications increased concurrent to launching the Section, providing a model for organizing GCs at institutions nationally and internationally. Highlighting such achievements will foster the expansion of GC roles in the era of precision genomic medicine and therapy. Considering ways to support GCs towards expanding these activities is equally important.

Risk of meningomyelocele mediated by the common 22q11.2 deletion.

Meningomyelocele is one of the most severe forms of neural tube defects (NTDs) and the most frequent structural birth defect of the central nervous system. We assembled the Spina Bifida Sequencing Consortium to identify causes. Exome and genome sequencing of 715 parent-offspring trios identified six patients with chromosomal 22q11.2 deletions, suggesting a 23-fold increased risk compared with the general population. Furthermore, analysis of a separate 22q11.2 deletion cohort suggested a 12- to 15-fold increased NTD risk of meningomyelocele. The loss of Crkl, one of several neural tube-expressed genes within the minimal deletion interval, was sufficient to replicate NTDs in mice, where both penetrance and expressivity were exacerbated by maternal folate deficiency. Thus, the common 22q11.2 deletion confers substantial meningomyelocele risk, which is partially alleviated by folate supplementation.