The purpose of this study is to analyze the prevalence of obesity in those affected by DDX3X-related neurodevelopmental disorder (DDX3X-NDD). Initial descriptions suggested that individuals with DDX3X-NDD suffered from poor weight gain or failure to thrive in early childhood, likely in the setting of feeding difficulties and secondary to associated hypotonia. However, through a patient's parent, we came to learn that obesity was a common problem for older patients. To investigate this, we developed a survey to be distributed to caregivers of patients with DDX3X-NDD. The flyer contained a QR code to access an online and anonymous survey, with questions regarding the diagnosis of DDX3X-NDD and concerns about obesity in the affected child. Approximately 31% of the study population (n = 70) expressed concerns about obesity on the anonymous survey, and nearly half of this population found obesity to be a concern after the diagnosis of DDX3X-NDD. Common interventions that were implemented for obesity concerns included medications, visits with Endocrinology specialists, exercise regimens, and diet modifications. There is not a defined correlation between concerns for obesity and other medical diagnoses affecting this clinical symptom prevalence, since it is understood that autism can affect diet and weight. The degree of intellectual disability in those with obesity concerns and diagnoses of DDX3X-NDD was not established. Our findings suggest that while poor weight gain due to feeding difficulties in infancy is common, obesity is a common health concern for older DDX3X-NDD patients.

The ARHGEF40 gene, also known as SOLO, encodes a RhoA-targeting guanine nucleotide exchange factor (GEF) and is currently considered a candidate gene with a potential relationship to disease. Our laboratory has confirmed variants at position p.Arg225 of the ARHGEF40 protein in multiple unrelated individuals with a phenotype including dysmorphic features, congenital anomalies and neurodevelopmental abnormalities. Here, we provide genetic and phenotypic information for two individuals harboring de novo variants at p.Arg225 and sharing a highly similar phenotype. This report suggests a relationship between variants at this amino acid position and autosomal dominant disease, and further studies will be needed to characterize this disease-gene relationship and elucidate the disease mechanism.

Background: Pierre Robin Sequence (PRS) presents in isolation [iPRS] or in conjunction with a genetic syndrome [sPRS] that can subsequently lead to respiratory dysfunction and eventual failure to thrive. Mandibular distraction osteogenesis (MDO) has gained popularity as a way to surgically address the airway obstruction in PRS. sPRS patients routinely have a more challenging clinical course, and there is a paucity of data comparing the effectiveness of MDO as a treatment for sPRS versus iPRS. That said, this study analyzed MDO in both sPRS and iPRS patients within a relatively large single institution cohort. Methods: A retrospective review was conducted on all PRS patients who underwent MDO by a single surgeon between 2015 and 2022. The patients were stratified into iPRS or sPRS based on genetic evaluation (N = 50). Primary measures were demographic and situational data; outcome measures included tracheostomy and gastrostomy tube (g-tube) avoidance, Apnea-Hypoxia Index (AHI), and laryngeal view predistraction and at time of distractor removal. Results: Prior to distraction, iPRS (N = 32) and sPRS (N = 18) patients showed no significant differences in age (105.1 ± 199.7 days; range 2-1051 days), AHI (17.3 ± 17.1; range 3.6-90), or laryngeal view (65% grade III or IV) ( P > .05). Overall, post-MDO, there was a statistically significant decrease in mean AHI 17.3 to 4.5 ( P < .001). sPRS patients in particular had a significant decrease in average AHI following MDO from 15.2 to 4.5 ( P = .028). Post-MDO both groups had similar improvement of laryngeal view, and avoidance of g-tube ( P < .05). Conclusions: MDO was found to be an effective technique to improve airway obstruction in both sPRS and iPRS. Despite the fact that sPRS patients typically have a more challenging clinical course, an equivalent clinical improvement in airway outcomes was seen between sPRS and iPRS patients post-MDO.

Craniofacial anomalies are a group of common congenital anomalies. They include orofacial clefts and craniosynostosis, which each may occur as an isolated anomaly or as part of a syndrome. There are hundreds of syndromes associated with craniofacial anomalies. Here we review a few select syndromes including 22q11.2 deletion syndrome, Van der Woude syndrome, Stickler syndrome, Trisomy 13, CHARGE syndrome, ectodermal dysplasias, Kabuki syndrome, and acrocephalosyndactyly syndromes. While most syndromes are associated with genetic etiologies, even isolated anomalies often have genetic components. Determining whether the anomaly is isolated, or part of a syndrome can provide prognostic, management, and recurrence information for families. The care team for an individual with a craniofacial anomaly includes a multitude of different subspecialists from a variety of fields including plastic surgery, oral and maxillofacial medicine, audiology, speech language pathology, otolaryngology, neurosurgery, genetics, pediatrics, social work, nutrition, and sleep medicine. A multidisciplinary care approach is beneficial, and ideally the care team can work together, communicate, and understand the different goals and scope of each team member. Genetics clinicians are a crucial part of the care team to determine the etiology of the anomaly and to inform the family and other subspecialists. Although the literature surrounding the genetic etiology of craniofacial anomalies continues to expand, limitations remain in the current understanding of genetic and other factors contributing to craniofacial anomalies.

PURPOSE OF REVIEW:A growing number of gene therapies are getting FDA-approved for pediatric rare disorders to treat once incurable diseases. Opportunities for preventing lifetime illness and improving quality of life for these patients is now becoming a reality. Challenges exist in navigating the complexities of determining which patients will benefit from these new gene therapies and how to effectively deliver them as a standard of care. RECENT FINDINGS:Gene therapies have been approved for pediatric hematological, neuromuscular, cancer, and other disorders that have improved the quality of life for rare disease patients. FDA approval of these drugs has been on a case-by-case basis leading towards gaps in drug approval, physician and patient knowledge of new gene therapies, and ultimate delivery of these drugs. Identifying patients that would benefit from these drugs and other coordination of care issues have arisen with each unique gene therapy product. These gene therapies have unique requirements and patient indications that require a knowledgeable group of physicians and hospital administrators to incorporate their use as a standard of care. With more gene therapies on the near horizon for FDA approval, multidisciplinary teams may improve patient access to these drugs by streamlining approaches towards adapting gene therapies into clinical use. SUMMARY:The rapid increase in the number of FDA-approved gene therapies has not only created a number of challenges but also opportunities to improve the lives of pediatric patients with rare disorders. The adaptability of physicians, hospitals, and governmental regulatory boards is essential for delivering these new gene therapies safely and efficiently to these rare disease patients. Challenges still remain as to future requirements for additional gene therapy dosing and how to best manage financial burdens placed on the patient and providing institution.

There is a shortage of clinical geneticists, even with concerted recruitment efforts. Previously, no data had been collected about why young career geneticists chose this specialty. To investigate this question, we carried out a survey of current and recent medical genetics and genomics residents. The goal of this survey was to understand their reasons for pursuing medical genetics and genomics as a specialty. Results demonstrate that, for most, interest in genetics begins in medical school and was largely influenced by mentorship. This suggests that placing greater focus on introducing medical genetics as a clinical specialty and fostering robust mentorship of students in preclinical years may increase recruitment into medical genetics residencies.

The ability to make informed decisions about reproductive health is a cornerstone principle of the practice of prenatal medical genetics. Unfortunately, these reproductive health decisions have become entangled in the current, contentious political climate. This debate reached an inflection point in 2022 with Dobbs v. Jackson when the Supreme Court of the United States (SCOTUS) overturned the national right to abortion previously established in Roe v. Wade. This decision prompted a reassessment of the opinions of medical students on reproductive health and abortion. Our study focused on a medical school in Alabama, a conservative state that enacted a restrictive abortion ban following the Dobbs ruling. Two surveys, conducted in 2015 and 2022, explored students' viewpoints on reproductive health topics, including abortion. The comparison revealed a significant shift toward more pro-choice perspectives among medical students. Notably, religious affiliation did not consistently align with opinions, as many Christian students supported pro-choice views. Our results suggest that medical students' reproductive health opinions at our institution have shifted to a more pro-choice position over the last decade.

We report 21 families displaying neurodevelopmental differences and multiple congenital anomalies while bearing a series of rare variants in mitogen-activated protein kinase kinase kinase kinase 4 ( MAP4K4 ). MAP4K4 has been implicated in many signaling pathways including c-Jun N-terminal and RAS kinases and is currently under investigation as a druggable target for multiple disorders. Using several zebrafish models, we demonstrate that these human variants are either loss-of-function or dominant-negative alleles and show that decreasing Map4k4 activity causes developmental defects. Furthermore, MAP4K4 can restrain hyperactive RAS signaling in early embryonic stages. Together, our data demonstrate that MAP4K4 negatively regulates RAS signaling in the early embryo and that variants identified in affected humans abrogate its function, establishing MAP4K4 as a causal locus for individuals with syndromic neurodevelopmental differences.

Heterogeneous nuclear ribonucleoprotein C (HNRNPC) is an essential, ubiquitously abundant protein involved in mRNA processing. Genetic variants in other members of the HNRNP family have been associated with neurodevelopmental disorders. Here, we describe 13 individuals with global developmental delay, intellectual disability, behavioral abnormalities, and subtle facial dysmorphology with heterozygous HNRNPC germline variants. Five of them bear an identical in-frame deletion of nine amino acids in the extreme C terminus. To study the effect of this recurrent variant as well as HNRNPC haploinsufficiency, we used induced pluripotent stem cells (iPSCs) and fibroblasts obtained from affected individuals. While protein localization and oligomerization were unaffected by the recurrent C-terminal deletion variant, total HNRNPC levels were decreased. Previously, reduced HNRNPC levels have been associated with changes in alternative splicing. Therefore, we performed a meta-analysis on published RNA-seq datasets of three different cell lines to identify a ubiquitous HNRNPC-dependent signature of alternative spliced exons. The identified signature was not only confirmed in fibroblasts obtained from an affected individual but also showed a significant enrichment for genes associated with intellectual disability. Hence, we assessed the effect of decreased and increased levels of HNRNPC on neuronal arborization and neuronal migration and found that either condition affects neuronal function. Taken together, our data indicate that HNRNPC haploinsufficiency affects alternative splicing of multiple intellectual disability-associated genes and that the developing brain is sensitive to aberrant levels of HNRNPC. Hence, our data strongly support the inclusion of HNRNPC to the family of HNRNP-related neurodevelopmental disorders.

American Journal of Medical Genetics Part C: Seminars in Medical GeneticsVolume 193, Issue 1 p. 1-2 ISSUE INFORMATIONFree Access Table of Contents, Volume 193, Number 1, March 2023 First published: 23 March 2023 https://doi.org/10.1002/ajmg.c.31974AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Volume193, Issue1Special Issue: Gene‐Targeted Therapies: Early Diagnosis and Equitable DeliveryMarch 2023Pages 1-2 RelatedInformation

aUniversity of Alabama at Birmingham, Departments of Genetics and Pediatrics bUniversity of Alabama at Birmingham, Department of Genetics, Birmingham, Alabama, USA Correspondence to Nathaniel H. Robin, MD, VH1L108B 1720 2nd Ave South, Birmingham, AL 35294, USA. Tel: +1 205 934 4983; fax: +1 205 975 3689; e-mail: [email protected]

PURPOSE:Multiple studies suggest an association between DLG2 and neurodevelopmental disorders and indicate the haploinsufficiency of this gene; however, few cases have been thoroughly described. We performed additional studies to confirm this clinical association and DLG2 haploinsufficiency. METHODS:Chromosomal microarray analysis was performed on 11,107 patients at the Cytogenetics Laboratory at the University of Alabama at Birmingham. The Database of Genomic Variants-Gold Standard Variants and the Genome Aggregation Database were selected for the association analysis. Fifty-nine patients from the literature and DECIPHER, all having DLG2 intragenic deletions, were included for comprehensive analysis of the distribution of these deletions. RESULTS:A total of 13 patients with DLG2 intragenic deletions, from 10 families in our cohort, were identified. Nine of 10 probands presented with clinical features of neurodevelopmental disorders. Congenital anomalies and dysmorphism were common in our cohort of patients. Association analysis showed that the frequency of DLG2 deletions in our cohort is significantly higher than those in the Database of Genomic Variants-Gold Standard Variants and the Genome Aggregation Database. Most of DLG2 intragenic deletions identified in 69 unrelated patients from our cohort, the literature, and DECIPHER map to the 5' region of the gene, with a hotspot centered around HPin7, exon 8, and HPin8. CONCLUSION:Our findings reinforce the link between DLG2 intragenic deletions and neurodevelopmental disorders, strongly support the haploinsufficiency of this gene, and indicate that these deletions might also have an association with congenital anomalies and dysmorphism.

Hearing loss is a common and complex condition that can occur at any age, can be inherited or acquired, and is associated with a remarkably wide array of etiologies. The diverse causes of hearing loss, combined with the highly variable and often overlapping presentations of different forms of hearing loss, challenge the ability of traditional clinical evaluations to arrive at an etiologic diagnosis for many deaf and hard-of-hearing individuals. However, identifying the etiology of hearing loss may affect clinical management, improve prognostic accuracy, and refine genetic counseling and assessment of the likelihood of recurrence for relatives of deaf and hard-of-hearing individuals. Linguistic and cultural identities associated with being deaf or hard-of-hearing can complicate access to and the effectiveness of clinical care. These concerns can be minimized when genetic and other health care services are provided in a linguistically and culturally sensitive manner. This clinical practice resource offers information about the frequency, causes, and presentations of hearing loss and suggests approaches to the clinical and genetic evaluation of deaf and hard-of-hearing individuals aimed at identifying an etiologic diagnosis and providing informative and effective patient education and genetic counseling.