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Purpose: MYRF-related cardiac-urogenital syndrome (MYRF-CUGS) is a rare condition associated with heterozygous MYRF variants. The description of MYRF-CUGS phenotype is mostly based on postnatal cases and 36 affected individuals have been published so far. We aim now to delineate the prenatal phenotype of MYRF-CUGS by reporting clinical data from fetuses and neonates with a pathogenic MYRF variant., Methods: Detailed radiographic, pathological, clinical, and molecular data from 12 prenatal cases were collected through an international collaborative study. Adding the five fetuses previously published, we were able to study a cohort of 17 cases., Results: Main ultrasound-accessible manifestations of MYRF-CUGS include congenital heart defects (13/17, 76%), congenital diaphragmatic hernia (10/17, 59%) and disorders of sexual differentiation in 46, XY fetuses (7/14; 50%). Postnatal examination and/or autopsy data highlighted additional birth defects and neurological findings with a large spectrum of severity. Molecular results revealed ten previously unpublished variants, one missense and nine predicted truncating variants (three frameshift, three nonsense and three splice site variants)., Conclusion: We report the first prenatal cohort of MYRF-CUGS, allowing us to further characterize the variable expressivity of this rare disorder in fetuses. Severe congenital anomalies with a poor prognosis are more frequent than previously described in postnatal cases. Our data suggest that MYRF-CUGS is characterized by a recurrent recognizable malformative association, accessible to prenatal diagnosis, with a significant intrafamilial phenotypic variability making genetic counseling challenging., (© 2024 The Author(s). Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Myhre syndrome (MS) is a rare genetic condition that presents with multiple genetic anomalies including cleft lip and palate and Eustachian tube dysfunction. These patients are at a high risk for airway scarring from intubation and mucosal inflammation. Hearing loss (conductive or mixed, of varying severity) is a common comorbidity in these patients, the exact etiology of which is still unclear. We present the cases of 2 unrelated children with MS who suffered progressive mixed hearing loss from fibrosis and obliteration of the middle ear spaces. Both patients had multiple sets of ear tubes that demonstrated early extrusion. The older patient underwent bone conduction implantation at age 11 which resulted in dramatic improvement of speech recognition and interactive skills. The other younger patient demonstrates a similar trajectory but has not yet undergone implantation. Otolaryngologists should take a cautious approach to surgery of the eardrum and middle ear to avoid unnecessary induction of fibrosis in this susceptible patient population. These cases highlight a newly described etiology for hearing loss and suggest a benefit to bone conduction implantation., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: Neurodevelopmental disorders (NDDs) often result from rare genetic variation, but genomic testing yield for NDDs remains below 50%, suggesting that clinically relevant variants may be missed by standard analyses. Here, we analyze "poison exons" (PEs), which are evolutionarily conserved alternative exons often absent from standard gene annotations. Variants that alter PE inclusion can lead to loss of function and may be highly penetrant contributors to disease., Methods: We curated published RNA sequencing data from developing mouse cortex to define 1937 conserved PE regions potentially relevant to NDDs, and we analyzed variants found by genome sequencing in multiple NDD cohorts., Results: Across 2999 probands, we found 6 novel clinically relevant variants in PE regions. Five of these variants are in genes that are part of the sodium voltage-gated channel alpha subunit family (SCN1A, SCN2A, and SCN8A), which is associated with epilepsies. One variant is in SNRPB, associated with cerebrocostomandibular syndrome. These variants have moderate to high computational impact assessments, are absent from population variant databases, and in genes with gene-phenotype associations consistent with each probands reported features., Conclusion: With a very minimal increase in variant analysis burden (average of 0.77 variants per proband), annotation of PEs can improve diagnostic yield for NDDs and likely other congenital conditions., Competing Interests: Conflict of Interest Eimear E. Kenny received personal fees from Illumina, 23andMe, and Regeneron Pharmaceuticals and serves as a scientific advisory board member for Encompass Bio, Foresite Labs, and Galateo Bio. All other authors declare no conflicts of interest., (Copyright © 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Background: It is critical to understand the wide-ranging clinical and non-clinical effects of genome sequencing (GS) for parents in the NICU context. We assessed parents' experiences with GS as a first-line diagnostic tool for infants with suspected genetic conditions in the NICU., Methods: Parents of newborns (N = 62) suspected of having a genetic condition were recruited across five hospitals in the southeast United States as part of the SouthSeq study. Semi-structured interviews (N = 78) were conducted after parents received their child's sequencing result (positive, negative, or variants of unknown significance). Thematic analysis was performed on all interviews., Results: Key themes included that (1) GS in infancy is important for reproductive decision making, preparing for the child's future care, ending the diagnostic odyssey, and sharing results with care providers; (2) the timing of disclosure was acceptable for most parents, although many reported the NICU environment was overwhelming; and (3) parents deny that receiving GS results during infancy exacerbated parent-infant bonding, and reported variable impact on their feelings of guilt., Conclusion: Parents reported that GS during the neonatal period was useful because it provided a "backbone" for their child's care. Parents did not consistently endorse negative impacts like interference with parent-infant bonding.

Background: The uptake of exome/genome sequencing has introduced unexpected testing results (incidental findings) that have become a major challenge for both testing laboratories and providers. While the American College of Medical Genetics and Genomics has outlined guidelines for laboratory management of clinically actionable secondary findings, debate remains as to whether incidental findings should be returned to patients, especially those representing pediatric populations., Methods: The Sequencing Analysis and Diagnostic Yield working group in the Clinical Sequencing Evidence-Generating Research Consortium has collected a cohort of pediatric patients found to harbor a genomic sequencing-identified non-ACMG-recommended incidental finding. The incidental variants were not thought to be associated with the indication for testing and were disclosed to patients and families., Results: In total, 23 "non-ACMG-recommended incidental findings were identified in 21 pediatric patients included in the study. These findings span four different research studies/laboratories and demonstrate differences in incidental finding return rate across study sites. We summarize specific cases to highlight core considerations that surround identification and return of incidental findings (uncertainty of disease onset, disease severity, age of onset, clinical actionability, and personal utility), and suggest that interpretation of incidental findings in pediatric patients can be difficult given evolving phenotypes. Furthermore, return of incidental findings can benefit patients and providers, but do present challenges., Conclusions: While there may be considerable benefit to return of incidental genetic findings, these findings can be burdensome to providers and present risk to patients. It is important that laboratories conducting genomic testing establish internal guidelines in anticipation of detection. Moreover, cross-laboratory guidelines may aid in reducing the potential for policy heterogeneity across laboratories as it relates to incidental finding detection and return. However, future discussion is required to determine whether cohesive guidelines or policy statements are warranted., (© 2022. The Author(s).)

Purpose: SouthSeq is a translational research study that undertook genome sequencing (GS) for infants with symptoms suggestive of a genetic disorder. Recruitment targeted racial/ethnic minorities and rural, medically underserved areas in the Southeastern United States, which are historically underrepresented in genomic medicine research., Methods: GS and analysis were performed for 367 infants to detect disease-causal variation concurrent with standard of care evaluation and testing., Results: Definitive diagnostic (DD) or likely diagnostic (LD) genetic findings were identified in 30% of infants, and 14% of infants harbored an uncertain result. Only 43% of DD/LD findings were identified via concurrent clinical genetic testing, suggesting that GS testing is better for obtaining early genetic diagnosis. We also identified phenotypes that correlate with the likelihood of receiving a DD/LD finding, such as craniofacial, ophthalmologic, auditory, skin, and hair abnormalities. We did not observe any differences in diagnostic rates between racial/ethnic groups., Conclusion: We describe one of the largest-to-date GS cohorts of ill infants, enriched for African American and rural patients. Our results show the utility of GS because it provides early-in-life detection of clinically relevant genetic variations not detected by current clinical genetic testing, particularly for infants exhibiting certain phenotypic features., Competing Interests: Conflict of Interest All authors declare no competing financial interests in relation to the work described., (Copyright © 2021 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Biallelic loss-of-function (LoF) variants in CENPF gene are responsible for Strømme syndrome, a condition presenting with intestinal atresia, anterior ocular chamber anomalies, and microcephaly. Through an international collaboration, four individuals (three males and one female) carrying CENPF biallelic variants, including two missense variants in homozygous state and four LoF variants, were identified by exome sequencing. All individuals had variable degree of developmental delay/intellectual disability and microcephaly (ranging from -2.9 SDS to -5.6 SDS) and a recognizable pattern of dysmorphic facial features including inverted-V shaped interrupted eyebrows, epicanthal fold, depressed nasal bridge, and pointed chin. Although one of the cases had duodenal atresia, all four individuals did not have the combination of internal organ malformations of Strømme syndrome (intestinal atresia and anterior eye segment abnormalities). Immunofluorescence analysis on skin fibroblasts on one of the four cases with the antibody for ARL13B that decorates primary cilia revealed shorter primary cilia that are consistent with a ciliary defect. This case-series of individuals with biallelic CENPF variants suggests the spectrum of clinical manifestations of the disorder that may be related to CENPF variants is broad and can include phenotypes lacking the cardinal features of Strømme syndrome., (© 2022 The Authors. American Journal of Medical Genetics Part C: Seminars in Medical Genetics published by Wiley Periodicals LLC.)

Background: Many infants in the neonatal intensive care unit (NICU) have genetic disorders or birth defects. The demand for genetic services is often complicated by a shortage of genetic providers., Problem: Our hospital experienced a significant reduction in genetic workforce, leading to insufficient genetic services to meet demand., Methods: The Plan-Do-Study-Act method of quality improvement was used to assess available resources, select an intervention plan, and collect patient outcome and provider satisfaction data., Intervention: An asynchronous telehealth model was deployed for clinical genetics consultations in our NICU utilizing a remote clinical geneticist., Results: The pilot study included 111 asynchronous telehealth consultations; 21% received a genetic diagnosis before discharge. Diagnoses were primarily chromosomal and single gene disorders. Referring NICU providers reported high satisfaction., Conclusion: Asynchronous telehealth for clinical genetics is a feasible and successful alternative to an on-site clinical geneticist and should be considered in areas with a genetic workforce shortage., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Genomic sequencing results need to be effectively communicated across all populations and practice settings. Projects in the Clinical Sequencing Evidence-Generating Research (CSER) consortium enroll diverse racial/ethnic and medically underserved participants across various clinical contexts. This article explores a set of CSER results disclosure cases to expand the evidence base on experiences returning genomic results. Case details were collected using a structured set of questions. We identified common themes in the case set, and assessed challenges and strategies in achieving six relevant results disclosure objectives. CSER-affiliated patient/community stakeholder impressions of the findings were solicited via video conference calls. Seventeen cases across six CSER projects were included. Case themes sorted into four categories: (1) factors influencing participant understanding, (2) participant emotional response, (3) disease burden, and (4) logistical challenges. Challenges meeting results disclosure objectives included a lack of dialogue, health literacy level, unexpected findings, and complex concepts. Strategies were consistent with traditional genetic counseling practice, but also highlighted approaches being evaluated in CSER projects. Patient/community stakeholders supported the identified themes and provided additional suggestions to improve patient understanding and engagement. These experiences add valuable insights into adapting genomic results disclosure practices to best serve all patient populations.

PurposeTo describe examples of missed pathogenic variants on whole-exome sequencing (WES) and the importance of deep phenotyping for further diagnostic testing.MethodsGuided by phenotypic information, three children with negative WES underwent targeted single-gene testing.ResultsIndividual 1 had a clinical diagnosis consistent with infantile systemic hyalinosis, although WES and a next-generation sequencing (NGS)-based ANTXR2 test were negative. Sanger sequencing of ANTXR2 revealed a homozygous single base pair insertion, previously missed by the WES variant caller software. Individual 2 had neurodevelopmental regression and cerebellar atrophy, with no diagnosis on WES. New clinical findings prompted Sanger sequencing and copy number testing of PLA2G6. A novel homozygous deletion of the noncoding exon 1 (not included in the WES capture kit) was detected, with extension into the promoter, confirming the clinical suspicion of infantile neuroaxonal dystrophy. Individual 3 had progressive ataxia, spasticity, and magnetic resonance image changes of vanishing white matter leukoencephalopathy. An NGS leukodystrophy gene panel and WES showed a heterozygous pathogenic variant in EIF2B5; no deletions/duplications were detected. Sanger sequencing of EIF2B5 showed a frameshift indel, probably missed owing to failure of alignment.ConclusionThese cases illustrate potential pitfalls of WES/NGS testing and the importance of phenotype-guided molecular testing in yielding diagnoses.

In order to describe the physical characteristics, medical complications, and natural history of classic 7q11.23 duplication syndrome [hereafter Dup7 (MIM 609757)], reciprocal duplication of the region deleted in Williams syndrome [hereafter WS (MIM 194050)], we systematically evaluated 53 individuals aged 1.25-21.25 years and 11 affected adult relatives identified in cascade testing. In this series, 27% of probands with Dup7 had an affected parent. Seven of the 26 de novo duplications that were examined for inversions were inverted; in all seven cases one of the parents had the common inversion polymorphism of the WS region. We documented the craniofacial features of Dup7: brachycephaly, broad forehead, straight eyebrows, broad nasal tip, low insertion of the columella, short philtrum, thin upper lip, minor ear anomalies, and facial asymmetry. Approximately 30% of newborns and 50% of older children and adults had macrocephaly. Abnormalities were noted on neurological examination in 88.7% of children, while 81.6% of MRI studies showed structural abnormalities such as decreased cerebral white matter volume, cerebellar vermis hypoplasia, and ventriculomegaly. Signs of cerebellar dysfunction were found in 62.3%, hypotonia in 58.5%, Developmental Coordination Disorder in 74.2%, and Speech Sound Disorder in 82.6%. Behavior problems included anxiety disorders, ADHD, and oppositional disorders. Medical problems included seizures, 19%; growth hormone deficiency, 9.4%; patent ductus arteriosus, 15%; aortic dilation, 46.2%; chronic constipation, 66%; and structural renal anomalies, 18%. We compare these results to the WS phenotype and offer initial recommendations for medical evaluation and surveillance of individuals who have Dup7., (© 2015 Wiley Periodicals, Inc.)

Mutations in ADNP were recently identified as a frequent cause of syndromic autism, characterized by deficits in social communication and interaction and restricted, repetitive behavioral patterns. Based on its functional domains, ADNP is a presumed transcription factor. The gene interacts closely with the SWI/SNF complex by direct and experimentally verified binding of its C-terminus to three of its core components. A detailed and systematic clinical assessment of the symptoms observed in our patients allows a detailed comparison with the symptoms observed in other SWI/SNF disorders. While the mutational mechanism of the first 10 patients identified suggested a gain of function mechanism, an 11th patient reported here is predicted haploinsufficient. The latter observation may raise hope for therapy, as addition of NAP, a neuroprotective octapeptide named after the first three amino acids of the sequence NAPVSPIQ, has been reported by others to ameliorate some of the cognitive abnormalities observed in a knockout mouse model. It is concluded that detailed clinical and molecular studies on larger cohorts of patients are necessary to establish a better insight in the genotype phenotype correlation and in the mutational mechanism., (© 2014 Wiley Periodicals, Inc.)

Context: Mutations in the electron donor enzyme P450 oxidoreductase (POR) result in congenital adrenal hyperplasia with apparent combined 17α-hydroxylase/17,20 lyase and 21-hydroxylase deficiencies, also termed P450 oxidoreductase deficiency (PORD). Major clinical features present in PORD are disordered sex development in affected individuals of both sexes, glucocorticoid deficiency, and multiple skeletal malformations., Objective: The objective of the study was to establish a noninvasive approach to prenatal diagnosis of PORD including assessment of malformation severity to facilitate optimized prenatal diagnosis and timely treatment., Design: We analyzed 20 pregnancies with children homozygous or compound heterozygous for disease-causing POR mutations and 1 pregnancy with a child carrying a heterozygous POR mutation by recording clinical and biochemical presentations and fetal ultrasound findings. In 4 of the pregnancies (3 homozygous and 1 heterozygous for disease-causing POR mutations), prenatal analysis of steroid metabolite excretion in maternal urine was carried out by gas chromatography/mass spectrometry during gestational weeks 11-23., Results: Pregnancy complications in our cohort included maternal virilization (6 of 20) with onset in the second trimester. Seven pregnant women presented with low unconjugated estriol at prenatal screening (triple or quadruple antenatal screening test). Overt dysmorphic features were noted in 19 of the 20 babies at birth but observed in only 5 by prenatal ultrasound. These 5 had the most severe malformation phenotypes and poor outcome, whereas the other babies showed normal development. Steroid profiling of maternal urine revealed significantly increased steroids of fetal origin, namely the pregnenolone metabolite epiallopregnanediol and the androgen metabolite androsterone, with concomitant low values for estriol. Diagnostic steroid ratios conclusively indicated PORD as early as gestational week 12. In the heterozygous pregnancy, steroid ratios were only slightly elevated and estriol excretion was normal., Conclusion: Prenatal diagnosis in PORD is readily established via urinary steroid metabolite analysis of maternal urine. Visible malformations at prenatal ultrasound predict a severe malformation phenotype.