Genetics evaluation outcomes of patients with pediatric hearing loss: 2008-2022 retrospective study.

OBJECTIVE: This study aims to explore how genetics evaluation and testing for patients with pediatric onset hearing loss affects their diagnosis and management. METHODS: Retrospective chart review was completed for patients with pediatric hearing loss that were evaluated by a genetic counselor from 2008 to 2022 with data entry into a REDCap database. Descriptive statistical analysis was completed. RESULTS: Four hundred twenty-nine patients with pediatric onset hearing loss were evaluated by genetics. Majority of patients presented with bilateral (67 %) and sensorineural (83 %) hearing loss. Genetic testing was recommended for 76 % of patients with pediatric hearing loss evaluated by a genetic counselor with 70 % completing some or all recommended tests. Overall genetic testing diagnostic rate was 34 %, with 41 % of diagnoses syndromic. Yearly trends noted an increasing number of patients evaluated, tests ordered, and subsequently an increased number of diagnoses overtime. For diagnostic results, management recommendations were made for 45 % of patients (35/78) and for 92 % of family members (72/78). This compared to total management recommendations for all patients (82/429, 19 %) and family members (110/429, 26 %). CONCLUSION: This study identified a genetic testing diagnostic rate for pediatric hearing loss of 34 % over 14 years. This study notes the beneficial outcomes of patients with hearing loss and their families meeting with a genetic counselor and the importance of collaboration with hearing loss management colleagues. It highlights the value a genetic counselor consult can add to a patient's diagnostic journey, in addition to how genetic testing impacts management for patients and their families.

Nonlethal presentations of CYP26B1-related skeletal anomalies and multiple synostoses syndrome.

Retinoic acid exposures as well as defects in the retinoic acid-degrading enzyme CYP26B1 have teratogenic effects on both limb and craniofacial skeleton. An initial report of four individuals described a syndrome of fetal and infantile lethality with craniosynostosis and skeletal anomalies caused by homozygous pathogenic missense variants in CYP26B1. In contrast, a 22-year-old female was reported with a homozygous missense pathogenic variant in CYP26B1 with complex multisuture craniosynostosis and intellectual disability, suggesting that in some cases, biallelic pathogenic variants of CYP26B1 may be compatible with life. Here we describe four additional living individuals from two families with compound heterozygous pathogenic missense variants in CYP26B1. Structural assessment of these additional missense variants places them further from the catalytic site and supports a model consistent with milder nonlethal disease. In addition to previously reported findings of multisuture craniosynostosis, conductive hearing loss, joint contractures, long slender fingers, camptodactly, broad fingertips, and developmental delay/intellectual disability, skeletal imaging in our cases also revealed gracile long bones, gracile ribs, radioulnar synostosis, and carpal and/or tarsal fusions. These individuals broaden the phenotypic range of biallelic pathogenic variants in CYPB26B1 and most significantly clarify that mortality can range from perinatal lethality to survival into adulthood.

EP300-related Rubinstein-Taybi syndrome: Highlighted rare phenotypic findings and a genotype-phenotype meta-analysis of 74 patients.

Pathogenic variants in the homologous and highly conserved genes-CREBBP and EP300-are causal for Rubinstein-Taybi syndrome (RSTS). CREBBP and EP300 encode histone acetyltransferases (HAT) that act as transcriptional co-activators, and their haploinsufficiency causes the pathology characteristic of RSTS by interfering with global transcriptional regulation. Though generally a well-characterized syndrome, there is a clear phenotypic spectrum; rare associations have emerged with increasing diagnosis that is critical for comprehensive understanding of this rare syndrome. We present 12 unreported patients with RSTS found to have EP300 variants discovered through gene sequencing and chromosomal microarray. Our cohort highlights rare phenotypic features associated with EP300 variants, including imperforate anus, retained fetal finger pads, and spina bifida occulta. Our findings support the previously noted prevalence of pregnancy-related hypertension/preeclampsia seen with this disease. We additionally performed a meta-analysis on our newly reported 12 patients and 62 of the 90 previously reported patients. We demonstrated no statistically significant correlation between phenotype severity (within the domains of intellectual disability and major organ involvement, as defined in our Methods section) and variant location and type; this is in contrast to the conclusions of some smaller studies and highlights the importance of large patient cohorts in characterization of this rare disease.

Phenotype delineation of ZNF462 related syndrome.

Zinc finger protein 462 (ZNF462) is a relatively newly discovered vertebrate specific protein with known critical roles in embryonic development in animal models. Two case reports and a case series study have described the phenotype of 10 individuals with ZNF462 loss of function variants. Herein, we present 14 new individuals with loss of function variants to the previous studies to delineate the syndrome of loss of function in ZNF462. Collectively, these 24 individuals present with recurring phenotypes that define a multiple congenital anomaly syndrome. Most have some form of developmental delay (79%) and a minority has autism spectrum disorder (33%). Characteristic facial features include ptosis (83%), down slanting palpebral fissures (58%), exaggerated Cupid's bow/wide philtrum (54%), and arched eyebrows (50%). Metopic ridging or craniosynostosis was found in a third of study participants and feeding problems in half. Other phenotype characteristics include dysgenesis of the corpus callosum in 25% of individuals, hypotonia in half, and structural heart defects in 21%. Using facial analysis technology, a computer algorithm applying deep learning was able to accurately differentiate individuals with ZNF462 loss of function variants from individuals with Noonan syndrome and healthy controls. In summary, we describe a multiple congenital anomaly syndrome associated with haploinsufficiency of ZNF462 that has distinct clinical characteristics and facial features.

Primary care physicians' understanding and utilization of pediatric exome sequencing results.

Optimizing exome sequencing (ES) utility requires effective communication and collaboration between primary care physicians (PCPs) and genetics healthcare providers (GHP). To explore how PCPs use ES results to coordinate multipart management plans for complex pediatric patients, we assessed result understanding and utilization. Twenty-seven PCPs of pediatric patients with ES results from a genetics clinic completed a mixed methods 45-question survey measuring perceived genetics knowledge, confidence performing genetics tasks, understanding of ES technology and results, and expectations of GHP. Quantitative and qualitative data analysis classified by ES result types generated descriptive statistics, Pearson correlation coefficients, and common themes. Forty-five-percent of PCPs interpreted variant of uncertain significance results as diagnostic (implementing management changes and recommending familial testing). Most PCPs (85%) identified positive ES results impacts, but only 65% indicated ES was beneficial to care. The majority (74%) expected GHP and patients' families to assume follow-up care responsibility and future ES results re-interpretations. Limited knowledge may be a factor, as 59% desired more patient care information from GHP. Our results suggest optimizing continuity of care and collaboration for pediatric patients with ES results requires additional communication between GHP and PCPs, along with continuing genetics education for PCPs aimed at improving genetic literacy.

Variable Clinical Manifestations of Xia-Gibbs syndrome: Findings of Consecutively Identified Cases at a Single Children's Hospital.

Xia-Gibbs syndrome (XGS) is a recently described neurodevelopmental disorder due to heterozygous loss-of-function AHDC1 mutations. XGS is characterized by global developmental delay, intellectual disability, hypotonia, and sleep abnormalities. Here we report the clinical phenotype of five of six individuals with XGS identified prospectively at the Children's Hospital of Philadelphia, a tertiary children's hospital in the USA. Although all five patients demonstrated common clinical features characterized by developmental delay and characteristic facial features, each of our patients showed unique clinical manifestations. Patient one had craniosynostosis; patient two had sensorineural hearing loss and bicuspid aortic valve; patient three had cutis aplasia; patient four had soft, loose skin; and patient five had a lipoma. Differential diagnoses considered for each patient were quite broad, and included craniosynostosis syndromes, connective tissue disorders, and mitochondrial disorders. Exome sequencing identified a heterozygous, de novo AHDC1 loss-of-function mutation in four of five patients; the remaining patient has a 357kb interstitial deletion of 1p36.11p35.3 including AHDC1. Although it remains unknown whether these unique clinical manifestations are rare symptoms of XGS, our findings indicate that the diagnosis of XGS should be considered even in individuals with additional non-neurological symptoms, as the clinical spectrum of XGS may involve such non-neurological manifestations. Adding to the growing literature on XGS, continued cohort studies are warranted in order to both characterize the clinical spectrum of XGS as well as determine standard of care for patients with this diagnosis.

Reclassification of Variants Following Renal Genetics Testing: Uncommon Yet Impactful for Diagnosis and Management.

Introduction: Genetic testing is increasingly utilized in nephrology practice, but limited real-world data exist on variant reclassification following renal genetics testing. Methods: A cohort of patients at the Cleveland Clinic Renal Genetics Clinic who underwent genetic testing through clinical laboratories was assessed with their clinical and laboratory data analyzed. Results: Between January 2019 and June 2023, 425 new patients with variable kidney disorders from 413 pedigrees completed genetic testing through 10 clinical laboratories, including 255 (60%) females with median (25th, 75th percentiles) age of 36 (22-54) years. Multigene panel was the most frequently used modality followed by single-gene testing, exome sequencing (ES), chromosomal microarray (CMA), and genome sequencing (GS). At initial report, 52% of patients had ≥1 variants of uncertain significance (VUS) with or without concurrent pathogenic variant(s). Twenty amendments were issued across 19 pedigrees involving 19 variants in 17 genes. The overall variant reclassification rate was 5%, with 63% being upgrades and 32% downgrades. Of the reclassified variants, 79% were initially reported as VUS. The median time-to-amendments from initial reports was 8.4 (4-27) months. Following the variant reclassifications, 60% of the patients received a new diagnosis or a change in diagnosis. Among these, 67% of patients received significant changes in clinical management. Conclusion: Variant reclassification following genetic testing is infrequent but important for diagnosis and management of patients with suspected genetic kidney disease. The majority of variant reclassifications involve VUS and are upgrades in clinically issued amended reports. Further studies are needed to investigate the predictors of such events.

Black Patients Equally Benefit From Renal Genetics Evaluation but Substantial Barriers in Access Exist.

Introduction: Genetic testing is increasingly accessible to patients with kidney diseases. Racial disparities in renal genetics evaluations have not been investigated. Methods: A cohort of patients evaluated by the Cleveland Clinic Renal Genetics Clinic (RGC) from January 2019 to March 2022 was analyzed. Results: Forty-eight Black patients, including 27 (56.3%) males, median age 34 (22-49) years and 232 White patients, including 76 (32.8%) males, median age 35 (21-53) years, were evaluated. Black patients were more likely to have end-stage kidney disease (ESKD) at the time of referral compared with White patients (23% vs. 7.3%, P = 0.004), more likely to be covered by Medicaid (46% vs. 15%, P < 0.001), and less likely to be covered by private insurance (35% vs. 66%, P < 0.001). Black patients were more likely to "no show" to scheduled appointment(s) or not submit specimens for genetic testing compared with White patients (24.1% vs. 6.7%, P = 0.0005). Genetic testing was completed in 35 Black patients. Of these, 37% had a positive result with 9 unique monogenic disorders and 1 chromosomal disorder diagnosed. Sixty-nine percent of Black patients with positive results received a new diagnosis or a change in diagnosis. Of these, 44% received a significant change in disease management. No differences in diagnostic yield and implications of management were noted between Black and White patients. Conclusion: Black patients equally benefit from renal genetics evaluation, but barriers to access exist. Steps must be taken to ensure equitable and early access for all patients. Further studies investigating specific interventions to improve access are needed.

Renal Genetics Clinic: 3-Year Experience in the Cleveland Clinic.

Rationale & Objective: There has been an increasing demand for the expertise provided by a renal genetics clinic. Such programs are limited in the United States and typically operate in a genomics research setting. Here we report a 3-year, real-world, single-center renal genetics clinic experience. Study Design: Retrospective cohort. Setting & Participants: Outpatient cases referred to the renal genetics clinic of the Cleveland Clinic between January 2019 and March 2022 were reviewed. Analytical Approach: Clinical and laboratory characteristics were analyzed. All genetic testing was performed in clinical labs. Results: 309 new patients referred from 15 specialties were evaluated, including 118 males and 191 females aged 35.1 ± 20.3 years. Glomerular diseases were the leading presentation followed by cystic kidney diseases, electrolyte disorders, congenital anomalies of kidneys and urinary tract, nephrolithiasis, and tubulointerstitial kidney diseases. Dysmorphic features were noted in 27 (8.7%) patients. Genetic testing was recommended in 292 (94.5%) patients including chromosomal microarray (8.9%), single-gene tests (19.5%), multigene panels (77.3%), and exome sequencing (17.5%). 80.5% of patients received insurance coverage for genetic testing. 45% (115/256) of patients had positive results, 25% (64/256) had variants of unknown significance, and 22.3% (57/256) had negative results. 43 distinct monogenic disorders were diagnosed. Family history of kidney disease was present in 52.8% of patients and associated with positive genetic findings (OR, 2.28; 95% CI, 1.40-3.74). 69% of patients with positive results received a new diagnosis and/or a change in the diagnosis. Among these, 39.7% (31/78) of patients received a significant change in disease management. Limitations: Retrospective and single-center study. Conclusions: The renal genetics clinic plays important roles in the diagnosis and management of patients with genetic kidney diseases. Multigene panels are the most frequently used testing modality with a high diagnostic yield. Family history of kidney disease is a strong indication for renal genetics clinic referral.

Further evidence of GABRA4 and TOP3B as autism susceptibility genes.

Chromosomal copy number variants (CNVs) are known contributors to neurodevelopmental conditions such as autism spectrum disorder (ASD). Both array comparative genomic hybridization and next-generation sequencing techniques have led to an increased detection of small CNVs and the identification of many candidate susceptibility genes for ASD. We report familial inheritance of two CNVs that include genes with known involvement in neurodevelopment. These CNVs are found in various combinations among four siblings with autism spectrum disorder, as well as in their neurodevelopmentally normal parents. We describe a 2.4 Mb duplication of 4p12 to 4p11 that includes GABRA4 (OMIM: 137141) and other GABA receptor genes, as well as a 246 kb deletion at 22q11.22 involving the TOP3B gene (OMIM: 603582). The maternally inherited 4p duplication was detected in three siblings, two of whom also had the paternally inherited 22q11.22 deletion. The fourth sibling only had the 22q11.22 deletion. These CNVs have rarely been reported in the literature. Upon review, a single publication was found describing a similar 4p duplication in three generations of a family with neurodevelopmental and neuropsychiatric disorders, as well as in an unrelated patient with autism (Polan et al., 2014). TOP3B falls within the distal 22q11.22 microdeletion syndrome and has been associated with schizophrenia, neurodevelopmental disorders including epilepsy, and cardiac defects. The identification of this family contributes to the understanding of specific genetic contributors to neurodevelopmental disorders and an emerging phenotype associated with proximal 4p duplication.