The impact of clinical genome sequencing in a global population with suspected rare genetic disease.

There is mounting evidence of the value of clinical genome sequencing (cGS) in individuals with suspected rare genetic disease (RGD), but cGS performance and impact on clinical care in a diverse population drawn from both high-income countries (HICs) and low- and middle-income countries (LMICs) has not been investigated. The iHope program, a philanthropic cGS initiative, established a network of 24 clinical sites in eight countries through which it provided cGS to individuals with signs or symptoms of an RGD and constrained access to molecular testing. A total of 1,004 individuals (median age, 6.5 years; 53.5% male) with diverse ancestral backgrounds (51.8% non-majority European) were assessed from June 2016 to September 2021. The diagnostic yield of cGS was 41.4% (416/1,004), with individuals from LMIC sites 1.7 times more likely to receive a positive test result compared to HIC sites (LMIC 56.5% [195/345] vs. HIC 33.5% [221/659], OR 2.6, 95% CI 1.9-3.4, p < 0.0001). A change in diagnostic evaluation occurred in 76.9% (514/668) of individuals. Change of management, inclusive of specialty referrals, imaging and testing, therapeutic interventions, and palliative care, was reported in 41.4% (285/694) of individuals, which increased to 69.2% (480/694) when genetic counseling and avoidance of additional testing were also included. Individuals from LMIC sites were as likely as their HIC counterparts to experience a change in diagnostic evaluation (OR 6.1, 95% CI 1.1-∞, p = 0.05) and change of management (OR 0.9, 95% CI 0.5-1.3, p = 0.49). Increased access to genomic testing may support diagnostic equity and the reduction of global health care disparities.

Artificial Urinary Sphincter Complications: A Narrative Review.

Stress urinary incontinence is a financially burdensome and socially isolating problem and can be experienced by men as a result of radical prostatectomy, radiation therapy, or other urologic surgery. Artificial urinary sphincter (AUS) placement for stress urinary incontinence is considered the 'gold standard' for male stress urinary incontinence. While initially only placed by specialized prosthetic surgeons, changes in urologic training have made implantation of the device by general urologists more widespread. Additionally, even though a minority of urologists place the majority of implants, many urologists may find themselves caring for patients with these devices even if they have never placed them themselves. For this reason, it is paramount that the urologic surgeon implanting the device and those caring for patients with prostheses are familiar with the various perioperative and postoperative complications of AUS implantation. This review discusses the most commonly reported complications of AUS implantation as well as those that are rarely described. Knowledge of these potential complications is necessary in order to care for patients with urologic implants.

Characterization of the prenatal renal phenotype associated with 17q12, HNF1B, microdeletions.

OBJECTIVE: Recurrent deletions involving 17q12 are associated with a variety of clinical phenotypes, including congenital abnormalities of the kidney and urinary tract (CAKUT), maturity onset diabetes of the young, type 5, and neurodevelopmental disorders. Structural and/or functional renal disease is the most common phenotypic feature, although the prenatal renal phenotypes and the postnatal correlates have not been well characterized. METHOD: We reviewed pre- and postnatal medical records of 26 cases with prenatally or postnatally identified 17q12/HNF1B microdeletions (by chromosomal microarray or targeted gene sequencing), obtained through a multicenter collaboration. We specifically evaluated 17 of these cases (65%) with reported prenatal renal ultrasound findings. RESULTS: Heterogeneous prenatal renal phenotypes were noted, most commonly renal cysts (41%, n = 7/17) and echogenic kidneys (41%), although nonspecific dysplasia, enlarged kidneys, hydronephrosis, pelvic kidney with hydroureter, and lower urinary tract obstruction were also reported. Postnatally, most individuals developed renal cysts (73%, 11/15 live births), and there were no cases of end-stage renal disease during childhood or the follow-up period. CONCLUSION: Our findings demonstrate that copy number variant analysis to assess for 17q12 microdeletion should be considered for a variety of prenatally detected renal anomalies. It is important to distinguish 17q12 microdeletion from other etiologies of CAKUT as the prognosis for renal function and presence of associated findings are distinct and may influence pregnancy and postnatal management.

The INSIGHT project: reflections on the co-production of a quality recognition programme to showcase excellence in public involvement in health and care research.

BACKGROUND: The quality of Patient and Public Involvement (PPI) in healthcare research varies considerably and is frequently tokenistic. We aimed to co-produce the Insight | Public Involvement Quality Recognition and Awards programme, based on the UK Standards for Public Involvement (UKSPI) alongside an incremental scale designed by Expert Citizens (a lived experience-led community group), to incentivise and celebrate continuous improvement in PPI. METHODS: We used Task and Finish Groups (19/44 [43%] public contributor membership) to co-produce the programme which we piloted in three organisations with different healthcare research models. We used surveys and review sessions to capture learning and reflections. RESULTS: We co-created: (1) A Quality descriptor matrix comprising four incremental quality levels (Welcoming, Listening, Learning, Leading) for each UKSPI standard. (2) An assessment framework including guidance materials, self-assessment form and final report template. (3) An assessor training package. (4) The quality awards event format and nomination form. These materials were modified based on pilot-site feedback. Of survey respondents: 94.4% felt they had made at least 'Some' personal contribution (half said 'Quite a lot'/'A great deal'), 88.9% said they were 'Always'/'Often' able to express their views freely and, 100% stated the programme would have 'A lot of impact'/'Quite a bit of impact'. During the project, we identified the importance of taking time to explain project aims and contributor roles, adapting to the needs of individual contributors and, using smaller bespoke sessions outside the main Task and Finish Groups. CONCLUSIONS: We co-produced and piloted a quality recognition programme to incentivise and celebrate continuous quality improvement in PPI. One public contributor stated, "I feel strongly that the Insight framework and awards will raise awareness of the [public involvement] work going on in many community settings. [It] is likely to result in better sharing of positive practice, incentivising research groups of any size to start work or to improve the quality of [PPI] could be one of the main benefits. I'm excited that if this initiative takes off, regionally and then in the longer term nationally, it could be a significant step in advancing the [public] voice."

How researchers involve members of the public in health research varies widely. We developed a scheme that encourages researchers from any health research organisation to improve the quality of public involvement. We used joint workshops with researchers, health workers and members of the public to design the scheme. We then tested it in three research organisations. We recorded the experience of people taking part in the project to learn what went well and what could be improved. We looked at the six areas covered in the UK Standards for Public Involvement. For each area, we worked together to define four levels (Welcoming, Listening, Learning, Leading) of increasing quality. We designed the materials needed for organisations to take part in the scheme. We also created a training pack for assessors and the format of a celebration event. We modified the materials after testing them. We asked those who took part in the project, half of whom were lay members, what they thought. 94% felt they had made at least some personal contribution. 89% said they were often or always able to express their views freely. Everyone thought the project would have some degree of impact. Overall, those members of the public who took part said they enjoyed the process and felt that their views were listened to. Along the way, we learned that it was important to carefully explain the project's aims, be clear about roles and have 1to1 discussions outside the main workshops.

Genomic analyses in Cornelia de Lange Syndrome and related diagnoses: Novel candidate genes, genotype-phenotype correlations and common mechanisms.

Cornelia de Lange Syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder characterized by highly variable manifestations of growth and developmental delays, upper limb involvement, hypertrichosis, cardiac, gastrointestinal, craniofacial, and other systemic features. Pathogenic variants in genes encoding cohesin complex structural subunits and regulatory proteins (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major pathogenic contributors to CdLS. Heterozygous or hemizygous variants in the genes encoding these five proteins have been found to be contributory to CdLS, with variants in NIPBL accounting for the majority (>60%) of cases, and the only gene identified to date that results in the severe or classic form of CdLS when mutated. Pathogenic variants in cohesin genes other than NIPBL tend to result in a less severe phenotype. Causative variants in additional genes, such as ANKRD11, EP300, AFF4, TAF1, and BRD4, can cause a CdLS-like phenotype. The common role that these genes, and others, play as critical regulators of developmental transcriptional control has led to the conditions they cause being referred to as disorders of transcriptional regulation (or "DTRs"). Here, we report the results of a comprehensive molecular analysis in a cohort of 716 probands with typical and atypical CdLS in order to delineate the genetic contribution of causative variants in cohesin complex genes as well as novel candidate genes, genotype-phenotype correlations, and the utility of genome sequencing in understanding the mutational landscape in this population.

Further delineation of the CWC27-associated spliceosomeopathy: Case report and review of the literature.

Pre-mRNA splicing factors are crucial in regulating transcript diversity, by removing introns from eukaryotic transcripts, an essential step in gene expression. Splicing of pre-mRNA is catalyzed by spliceosomes. CWC27 is a cyclophilin associated with spliceosome, in which genetic defects of its components have been linked to spliceosomopathies with clinical phenotypes including skeletal developmental defects, retinitis pigmentosa (RP), short stature, skeletal anomalies, and neurological disorders. We report two siblings (male and female) of Mexican descent with a novel homozygous frameshift variant in CWC27 and aim to highlight the cardinal features among the previously described 12 cases as well as expand the currently recognized phenotypic spectrum. Both siblings presented with a range of ocular and extraocular manifestations including novel features such as solitary kidney and tarsal coalition in the male sibling, together with gait abnormalities, and Hashimoto's thyroiditis in the female sibling. Finally, we highlight ectodermal involvement including sparse scalp hair, eyebrows and lashes, pigmentary differences, nail dysplasia, and dental anomalies as a core phenotype associated with the CWC27 spliceosomopathy.

Insights into the perinatal phenotype of Kabuki syndrome in infants identified by genome-wide sequencing.

Increasing use of unbiased genomic sequencing in critically ill infants can expand understanding of rare diseases such as Kabuki syndrome (KS). Infants diagnosed with KS through genome-wide sequencing performed during the initial hospitalization underwent retrospective review of medical records. Human phenotype ontology terms used in genomic analysis were aggregated and analyzed. Clinicians were surveyed regarding changes in management and other care changes. Fifteen infants met inclusion criteria. KS was not suspected prior to genomic sequencing. Variants were classified as Pathogenic (n = 10) or Likely Pathogenic (n = 5) by American College of Medical Genetics and Genomics Guidelines. Fourteen variants were de novo (KMT2D, n = 12, KDM6A, n = 2). One infant inherited a likely pathogenic variant in KMT2D from an affected father. Frequent findings involved cardiovascular (14/15) and renal (7/15) systems, with palatal defects also identified (6/15). Three infants had non-immune hydrops. No minor anomalies were universally documented; ear anomalies, micrognathia, redundant nuchal skin, and hypoplastic nails were common. Changes in management were reported in 14 infants. Early use of unbiased genome-wide sequencing enabled a molecular diagnosis prior to clinical recognition including infants with atypical or rarely reported features of KS while also expanding the phenotypic spectrum of this rare disorder.

Biallelic PRMT7 pathogenic variants are associated with a recognizable syndromic neurodevelopmental disorder with short stature, obesity, and craniofacial and digital abnormalities.

PURPOSE: Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyzes the methylation of arginine residues on several protein substrates. Biallelic pathogenic PRMT7 variants have previously been associated with a syndromic neurodevelopmental disorder characterized by short stature, brachydactyly, intellectual developmental disability, and seizures. To our knowledge, no comprehensive study describes the detailed clinical characteristics of this syndrome. Thus, we aim to delineate the phenotypic spectrum of PRMT7-related disorder. METHODS: We assembled a cohort of 51 affected individuals from 39 different families, gathering clinical information from 36 newly described affected individuals and reviewing data of 15 individuals from the literature. RESULTS: The main clinical characteristics of the PRMT7-related syndrome are short stature, mild to severe developmental delay/intellectual disability, hypotonia, brachydactyly, and distinct facial morphology, including bifrontal narrowing, prominent supraorbital ridges, sparse eyebrows, short nose with full/broad nasal tip, thin upper lip, full and everted lower lip, and a prominent or squared-off jaw. Additional variable findings include seizures, obesity, nonspecific magnetic resonance imaging abnormalities, eye abnormalities (i.e., strabismus or nystagmus), and hearing loss. CONCLUSION: This study further delineates and expands the molecular, phenotypic spectrum and natural history of PRMT7-related syndrome characterized by a neurodevelopmental disorder with skeletal, growth, and endocrine abnormalities.

Identifying phenotypic expansions for congenital diaphragmatic hernia plus (CDH+) using DECIPHER data.

Congenital diaphragmatic hernia (CDH) can occur in isolation or in conjunction with other birth defects (CDH+). A molecular etiology can only be identified in a subset of CDH cases. This is due, in part, to an incomplete understanding of the genes that contribute to diaphragm development. Here, we used clinical and molecular data from 36 individuals with CDH+ who are cataloged in the DECIPHER database to identify genes that may play a role in diaphragm development and to discover new phenotypic expansions. Among this group, we identified individuals who carried putatively deleterious sequence or copy number variants affecting CREBBP, SMARCA4, UBA2, and USP9X. The role of these genes in diaphragm development was supported by their expression in the developing mouse diaphragm, their similarity to known CDH genes using data from a previously published and validated machine learning algorithm, and/or the presence of CDH in other individuals with their associated genetic disorders. Our results demonstrate how data from DECIPHER, and other public databases, can be used to identify new phenotypic expansions and suggest that CREBBP, SMARCA4, UBA2, and USP9X play a role in diaphragm development.

X-linked neonatal-onset epileptic encephalopathy associated with a gain-of-function variant p.R660T in GRIA3.

The X-linked GRIA3 gene encodes the GLUA3 subunit of AMPA-type glutamate receptors. Pathogenic variants in this gene were previously reported in neurodevelopmental diseases, mostly in male patients but rarely in females. Here we report a de novo pathogenic missense variant in GRIA3 (c.1979G>C; p. R660T) identified in a 1-year-old female patient with severe epilepsy and global developmental delay. When exogenously expressed in human embryonic kidney (HEK) cells, GLUA3_R660T showed slower desensitization and deactivation kinetics compared to wildtype (wt) GLUA3 receptors. Substantial non-desensitized currents were observed with the mutant but not for wt GLUA3 with prolonged exposure to glutamate. When co-expressed with GLUA2, the decay kinetics were similarly slowed in GLUA2/A3_R660T with non-desensitized steady state currents. In cultured cerebellar granule neurons, miniature excitatory postsynaptic currents (mEPSCs) were significantly slower in R660T transfected cells than those expressing wt GLUA3. When overexpressed in hippocampal CA1 neurons by in utero electroporation, the evoked EPSCs and mEPSCs were slower in neurons expressing R660T mutant compared to those expressing wt GLUA3. Therefore our study provides functional evidence that a gain of function (GoF) variant in GRIA3 may cause epileptic encephalopathy and global developmental delay in a female subject by enhancing synaptic transmission.

Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome.

Wiedemann-Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype-phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty-nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non-LoF variants. This study identifies genotype-phenotype correlations as well as race-facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long-term outcomes in individuals with WSS.

Postmortem diagnosis of PPA2-associated sudden cardiac death from dried blood spot in a neonate presenting with vocal cord paralysis.

Biallelic variants in inorganic pyrophosphatase 2 (PPA2) are known to cause infantile sudden cardiac failure (OMIM #617222), but relatively little is known about phenotypic variability of these patients prior to their death. We report a 5-wk-old male with bilateral vocal cord paralysis and hypertension who had a sudden unexpected cardiac death. Subsequently, molecular autopsy via whole-genome sequencing from newborn dried blood spot identified compound heterozygous mutations in PPA2, with a paternally inherited, pathogenic missense variant (c.514G > A; p.Glu172Lys) and a novel, maternally inherited missense variant of uncertain significance (c.442A > T; p.Thr148Ser). This report expands the presenting phenotype of patients with PPA2 variants. It also highlights the utility of dried blood spots for postmortem molecular diagnosis.

Ultrasound and Magnetic Resonance Imaging of Agenesis of the Corpus Callosum in Fetuses: Frontal Horns and Cavum Septi Pellucidi Are Clues to Earlier Diagnosis.

OBJECTIVES: We hypothesized that: (1) fetal frontal horn (FH) morphology and their proximity to the cavum septi pellucidi (CSP) can assist in suspecting complete agenesis of the corpus callosum (cACC) and partial agenesis of the corpus callosum (pACC) earlier than known indirect ultrasound (US) findings; (2) FHs assist in differentiating a true CSP from a pseudocavum; and (3) magnetic resonance imaging (MRI) is useful in learning FH morphology and pseudocavum etiology. METHODS: Thirty-two patients with cACC and 9 with pACC were identified on an Institutional Review Board-approved retrospective review. Of the 41 cases, 40 had prenatal US, and 21 had prenatal MRI; 17 had follow-up neonatal US, and 14 had follow-up neonatal MRI. Variables evaluated retrospectively were the presence of a CSP or a pseudocavum, ventricle size and shape, and FH shape (comma, trident, parallel, golf club, enlarged, or fused). Displacement between the inferior edge of the FH and the midline or cavum/pseudocavum was measured. RESULTS: Fetal FHs had an abnormal shape in 77% ≤20 weeks' gestation, 86% ≤24 weeks, and 90% >24 weeks. Frontal horns were laterally displaced greater than 2 mm in 85% ≤20 weeks, 91% ≤24 weeks, and 95% >24 weeks. The CSP was absent in 100% of cACC cases and 78% of pACC cases, and a pseudocavum was present in 88% of cACC cases and 78% of pACC cases across gestation. Magnetic resonance imaging confirmed US pseudocavums to be focal interhemispheric fluid or an elevated/dilated third ventricle. CONCLUSIONS: Frontal horns assist in assessing ACC ≤24 weeks and throughout gestation. Pseudocavums, often simulating CSPs, are common in ACC. Frontal horn lateral displacement and abnormal morphology, recognized by MRI correlations, are helpful in differentiating a pseudocavum from a true CSP. A normal CSP should not be cleared on screening US unless normally shaped FHs are seen directly adjacent to it.

Health Supervision for People With Achondroplasia.

Achondroplasia is the most common short-stature skeletal dysplasia, additionally marked by rhizomelia, macrocephaly, midface hypoplasia, and normal cognition. Potential medical complications associated with achondroplasia include lower extremity long bone bowing, middle-ear dysfunction, obstructive sleep apnea, and, more rarely, cervicomedullary compression, hydrocephalus, thoracolumbar kyphosis, and central sleep apnea. This is the second revision to the original 1995 health supervision guidance from the American Academy of Pediatrics for caring for patients with achondroplasia. Although many of the previously published recommendations remain appropriate for contemporary medical care, this document highlights interval advancements in the clinical methods available to monitor for complications associated with achondroplasia. This document is intended to provide guidance for health care providers to help identify individual patients at high risk of developing serious sequelae and to enable intervention before complications develop.

Loss-of-Function Variants in PPP1R12A: From Isolated Sex Reversal to Holoprosencephaly Spectrum and Urogenital Malformations.

In two independent ongoing next-generation sequencing projects for individuals with holoprosencephaly and individuals with disorders of sex development, and through international research collaboration, we identified twelve individuals with de novo loss-of-function (LoF) variants in protein phosphatase 1, regulatory subunit 12a (PPP1R12A), an important developmental gene involved in cell migration, adhesion, and morphogenesis. This gene has not been previously reported in association with human disease, and it has intolerance to LoF as illustrated by a very low observed-to-expected ratio of LoF variants in gnomAD. Of the twelve individuals, midline brain malformations were found in five, urogenital anomalies in nine, and a combination of both phenotypes in two. Other congenital anomalies identified included omphalocele, jejunal, and ileal atresia with aberrant mesenteric blood supply, and syndactyly. Six individuals had stop gain variants, five had a deletion or duplication resulting in a frameshift, and one had a canonical splice acceptor site loss. Murine and human in situ hybridization and immunostaining revealed PPP1R12A expression in the prosencephalic neural folds and protein localization in the lower urinary tract at critical periods for forebrain division and urogenital development. Based on these clinical and molecular findings, we propose the association of PPP1R12A pathogenic variants with a congenital malformations syndrome affecting the embryogenesis of the brain and genitourinary systems and including disorders of sex development.

Partial Jacobsen syndrome phenotype in a patient with a de novo frameshift mutation in the ETS1 transcription factor.

Jacobsen syndrome (OMIM #147791) is a rare contiguous gene disorder caused by deletions in distal 11q. The clinical phenotype is variable and can include dysmorphic features, varying degrees of intellectual disability, behavioral problems including autism and attention deficit hyperactivity disorder, congenital heart defects, structural kidney defects, genitourinary problems, immunodeficiency, and a bleeding disorder due to impaired platelet production and function. Previous studies combining both human and animal systems have implicated several disease-causing genes in distal 11q that contribute to the Jacobsen syndrome phenotype. One gene, ETS1, has been implicated in causing congenital heart defects, structural kidney defects, and immunodeficiency. We performed a comprehensive phenotypic analysis on a patient with congenital heart disease previously found to have a de novo frameshift mutation in ETS1, resulting in the loss of the DNA-binding domain of the protein. Our results suggest that loss of Ets1 causes a "partial Jacobsen syndrome phenotype" including congenital heart disease, facial dysmorphism, intellectual disability, and attention deficit hyperactivity disorder.

Further phenotypic characterization of Kaufman oculocerebrofacial syndrome: report of five new cases and literature review.

Kaufman oculocerebrofacial syndrome is a rare autosomal recessive disorder caused by biallelic variants in UBE3B. Kaufman oculocerebrofacial syndrome is characterized by a recognizable pattern of malformations including moderate to severe intellectual disability, growth deficiency, microcephaly and a distinctive facial gestalt. Common craniofacial features include short upslanting palpebral fissures, blepharophimosis or ptosis, ear anomalies, hearing loss, palate anomalies and stridor/laryngomalacia. The aim of this study was to describe the phenotypic features and the genotype of five new individuals from three unrelated families, and to review systematically the published information of 26 cases. The main features are summarized contributing to further characterize the natural history of the disease. Novel phenotypic features and two novel pathogenic variants in UBE3B are reported: A splice site variant (c.2569-1G > C) and a nonsense variant (c.518C > A, p.Ser173Ter). Kaufman oculocerebrofacial syndrome is likely an underdiagnosed disorder which can be clinically recognized based on its distinctive facial gestalt and relatively homogenous natural history.

Case for genome sequencing in infants and children with rare, undiagnosed or genetic diseases.

Up to 350 million people worldwide suffer from a rare disease, and while the individual diseases are rare, in aggregate they represent a substantial challenge to global health systems. The majority of rare disorders are genetic in origin, with children under the age of five disproportionately affected. As these conditions are difficult to identify clinically, genetic and genomic testing have become the backbone of diagnostic testing in this population. In the last 10 years, next-generation sequencing technologies have enabled testing of multiple disease genes simultaneously, ranging from targeted gene panels to exome sequencing (ES) and genome sequencing (GS). GS is quickly becoming a practical first-tier test, as cost decreases and performance improves. A growing number of studies demonstrate that GS can detect an unparalleled range of pathogenic abnormalities in a single laboratory workflow. GS has the potential to deliver unbiased, rapid and accurate molecular diagnoses to patients across diverse clinical indications and complex presentations. In this paper, we discuss clinical indications for testing and historical testing paradigms. Evidence supporting GS as a diagnostic tool is supported by superior genomic coverage, types of pathogenic variants detected, simpler laboratory workflow enabling shorter turnaround times, diagnostic and reanalysis yield, and impact on healthcare.

Whole-exome sequencing reveals novel USP9X variant in female fetus with isolated agenesis of the corpus callosum.

Whole-exome sequencing in a female fetus detected a USP9X variant. This X-linked gene was recently associated with intellectual disability and distinct pattern of malformation in females. Isolated agenesis of the corpus callosum has not been reported in association with USP9X. Identifying this variant impacted management of the subsequent pregnancy.