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.

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.

Lymphatic disorders caused by mosaic, activating KRAS variants respond to MEK inhibition.

Central conducting lymphatic anomaly (CCLA) due to congenital maldevelopment of the lymphatics can result in debilitating and life-threatening disease with limited treatment options. We identified 4 individuals with CCLA, lymphedema, and microcystic lymphatic malformation due to pathogenic, mosaic variants in KRAS. To determine the functional impact of these variants and identify a targeted therapy for these individuals, we used primary human dermal lymphatic endothelial cells (HDLECs) and zebrafish larvae to model the lymphatic dysplasia. Expression of the p.Gly12Asp and p.Gly13Asp variants in HDLECs in a 2­dimensional (2D) model and 3D organoid model led to increased ERK phosphorylation, demonstrating these variants activate the RAS/MAPK pathway. Expression of activating KRAS variants in the venous and lymphatic endothelium in zebrafish resulted in lymphatic dysplasia and edema similar to the individuals in the study. Treatment with MEK inhibition significantly reduced the phenotypes in both the organoid and the zebrafish model systems. In conclusion, we present the molecular characterization of the observed lymphatic anomalies due to pathogenic, somatic, activating KRAS variants in humans. Our preclinical studies suggest that MEK inhibition should be studied in future clinical trials for CCLA due to activating KRAS pathogenic variants.

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.

Prenatal Screening and Diagnostic Considerations for 22q11.2 Microdeletions.

Diagnosis of a chromosome 22q11.2 microdeletion and its associated deletion syndrome (22q11.2DS) is optimally made early. We reviewed the available literature to provide contemporary guidance and recommendations related to the prenatal period. Indications for prenatal diagnostic testing include a parent or child with the 22q11.2 microdeletion or suggestive prenatal screening results. Definitive diagnosis by genetic testing of chorionic villi or amniocytes using a chromosomal microarray will detect clinically relevant microdeletions. Screening options include noninvasive prenatal screening (NIPS) and imaging. The potential benefits and limitations of each screening method should be clearly conveyed. NIPS, a genetic option available from 10 weeks gestational age, has a 70-83% detection rate and a 40-50% PPV for most associated 22q11.2 microdeletions. Prenatal imaging, usually by ultrasound, can detect several physical features associated with 22q11.2DS. Findings vary, related to detection methods, gestational age, and relative specificity. Conotruncal cardiac anomalies are more strongly associated than skeletal, urinary tract, or other congenital anomalies such as thymic hypoplasia or cavum septi pellucidi dilatation. Among others, intrauterine growth restriction and polyhydramnios are additional associated, prenatally detectable signs. Preconception genetic counselling should be offered to males and females with 22q11.2DS, as there is a 50% risk of transmission in each pregnancy. A previous history of a de novo 22q11.2 microdeletion conveys a low risk of recurrence. Prenatal genetic counselling includes an offer of screening or diagnostic testing and discussion of results. The goal is to facilitate optimal perinatal care.

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 impact of in utero transfusions on perinatal outcomes in patients with alpha thalassemia major: the UCSF registry.

Alpha thalassemia major (ATM) is a hemoglobinopathy that usually results in perinatal demise if in utero transfusions (IUTs) are not performed. We established an international registry (NCT04872179) to evaluate the impact of IUTs on survival to discharge (primary outcome) as well as perinatal and neurodevelopmental secondary outcomes. Forty-nine patients were diagnosed prenatally, 11 were diagnosed postnatally, and all 11 spontaneous survivor genotypes had preserved embryonic zeta-globin levels. We compared 3 groups of patients; group 1, prenatally diagnosed and alive at hospital discharge (n = 14), group 2, prenatally diagnosed and deceased perinatally (n = 5), and group 3, postnatally diagnosed and alive at hospital discharge (n = 11). Group 1 had better outcomes than groups 2 and 3 in terms of the resolution of hydrops, delivery closer to term, shorter hospitalizations, and more frequent average or greater neurodevelopmental outcomes. Earlier IUT initiation was correlated with higher neurodevelopmental (Vineland-3) scores (r = -0.72, P = .02). Preterm delivery after IUT was seen in 3/16 (19%) patients who continued their pregnancy. When we combined our data with those from 2 published series, patients who received ≥2 IUTs had better outcomes than those with 0 to 1 IUT, including resolution of hydrops, delivery at ≥34 weeks gestation, and 5-minute appearance, pulse, grimace, activity, and respiration scores ≥7. Neurodevelopmental assessments were normal in 17/18 of the ≥2 IUT vs 5/13 of the 0 to 1 IUT group (OR 2.74; P = .01). Thus, fetal transfusions enable the survival of patients with ATM and normal neurodevelopment, even in those patients presenting with hydrops. Nondirective prenatal counseling for expectant parents should include the option of IUTs.

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.

Improved Outcomes in Patients with 22q11.2 Deletion Syndrome and Diagnosis of Interrupted Aortic Arch Prior to Birth Hospital Discharge, a Retrospective Study.

Interruption of the aortic arch (IAA) is a rare but life-threatening congenital heart defect if not corrected in the neonatal period. IAA type B is highly correlated with 22q11.2 deletion syndrome (22q11.2DS); approximately 50% of patients with IAA type B also have 22q11.2DS (Peyvandi et al.; Goldmuntz et al.). Early identification and repair of IAA can prevent severe morbidity and death. However, IAA is challenging to identify prenatally, or even in the neonatal period. In this study, we examined infants with IAA, diagnosed during pregnancy and prior to discharge (PPTD) from the birth hospital vs. those diagnosed following discharge (FD) from the newborn nursery. Our goals were to determine: (1) if early diagnosis improved outcomes; and (2) if patients with IAA and without 22q11.2DS had similar outcomes. In total, 135 patients with a diagnosis of 22q11.2DS and IAA were ascertained through the 22q and You Center at the Children's Hospital of Philadelphia (CHOP). The examined outcomes included: timing of diagnosis; age at diagnosis (days); hospital length of stay (LOS); duration of intensive care unit (ICU) stay; mechanical ventilation (days); duration of inotrope administration (days); year of surgical intervention; birth hospital trauma level; and overall morbidity. These outcomes were then compared with 40 CHOP patients with IAA but without 22q11.2DS. The results revealed that the PPTD neonates had fewer days of intubation, inotrope administration, and hospital LOS when compared to the FD group. The outcomes between deleted and non-deleted individuals with IAA differed significantly, in terms of the LOS (40 vs. 39 days) and time in ICU (28 vs. 24 days), respectively. These results support the early detection of 22q11.2DS via prenatal screening/diagnostics/newborn screening, as IAA can evade routine prenatal ultrasound and postnatal pulse oximetry. However, as previously reported in patients with 22q11.2DS and congenital heart disease (CHD), patients with 22q11.2DS tend to fare poorer compared to non-deleted neonates with IAA.

'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.

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.

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.

Autism spectrum disorder and neurodevelopmental delays in children with giant omphalocele.

OBJECTIVE: To determine the prevalence and identify risk factors of autism spectrum disorders (ASDs) and neurodevelopmental delays in giant omphalocele (GO) survivors. MATERIALS AND METHODS: The study cohort consists of 47 GO survivors enrolled in our follow-up program between 07/2004 and 12/2015. All patients underwent assessments at 2 years of age or older. Outcomes were assessed by either the Bayley Scales of Infant Development II (prior 2006) or III (after 2006), or the Wechsler Preschool and Primary Scale of Intelligence (children older than 4 years). ASD diagnosis was made based on the Diagnostic and Statistical Manual of Mental Disorders IV (prior to 2014) or 5 criteria. RESULTS: The prevalence of ASD in GO children is 16 times higher than the general population (P = 0.0002). ASD patients were more likely to be diagnosed with neurodevelopmental and neurofunctional delays, language disorders, and genetic abnormalities (P < 0.01). While 53.2% of GO children scored within the average range for all developmental domains, 19.1% scored within the mildly delayed and 27.7% in the severe delayed range in at least one domain. Prolonged respiratory support, pulmonary hypertension, gastroesophageal reflux disease, feeding problems, prolonged hospitalization, abnormal BAER hearing screen, presence of delayed motor coordination, and hypotonicity were associated with delayed scores (P < 0.05). CONCLUSIONS: There is a significant rate of ASD in GO survivors. Neurodevelopmental delays, language delays, and genetic abnormalities were strongly associated with ASD. Neurological impairments were present in nearly half of GO children. Surrogate markers of disease severity were associated with below average neurodevelopmental scores. Level of evidence Level IV.

Molecular diagnosis of somatic overgrowth conditions: A single-center experience.

BACKGROUND: Somatic overgrowth conditions, including Proteus syndrome, Sturge-Weber syndrome, and PIK3CA-related overgrowth spectrum, are caused by post-zygotic pathogenic variants, result in segmental mosaicism, and give rise to neural, cutaneous and/or lipomatous overgrowth. These variants occur in growth-promoting pathways leading to cellular proliferation and expansion of tissues that arise from the affected cellular lineage. METHODS: We report on 80 serial patients evaluated for somatic overgrowth conditions in a diagnostic laboratory setting, including three prenatal patients. In total, 166 tissues from these 80 patients were subjected to targeted sequencing of an 8-gene panel capturing 10.2 kb of sequence containing known pathogenic variants associated with somatic overgrowth conditions. Deep next-generation sequencing was performed with the IonTorrent PGM platform at an average depth typically >5,000×. RESULTS: Likely pathogenic or pathogenic variants were identified in 36 individuals and variants of unknown significance in four. The overall molecular diagnostic yield was 45% but was highly influenced by both submitted tissue type and phenotype. In the prenatal setting, two patients had pathogenic variants identified in cultured amniocytes but in a third patient, the pathogenic variant was only present in post-natal tissues. Finally, expanding the test to include full gene sequencing of PIK3CA in contrast to targeted sequencing identified likely pathogenic variants in 3 of 7 patients that tested negative on the original panel. CONCLUSION: Next-generation sequencing has enabled sensitive detection of somatic pathogenic variants associated with overgrowth conditions. However, as the pathogenic variant allele frequency varies by tissue type within an individual, submission of affected tissue(s) greatly increases the chances of a molecular diagnosis.

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.