Burden re-analysis of neurodevelopmental disorder cohorts for prioritization of candidate genes.

This study aimed to uncover novel genes associated with neurodevelopmental disorders (NDD) by leveraging recent large-scale de novo burden analysis studies to enhance a virtual gene panel used in a diagnostic setting. We re-analyzed historical trio-exome sequencing data from 745 individuals with NDD according to the most recent diagnostic standards, resulting in a cohort of 567 unsolved individuals. Next, we designed a virtual gene panel containing candidate genes from three large de novo burden analysis studies in NDD and prioritized candidate genes by stringent filtering for ultra-rare de novo variants with high pathogenicity scores. Our analysis revealed an increased burden of de novo variants in our selected candidate genes within the unsolved NDD cohort and identified qualifying de novo variants in seven candidate genes: RIF1, CAMK2D, RAB11FIP4, AGO3, PCBP2, LEO1, and VCP. Clinical data were collected from six new individuals with de novo or inherited LEO1 variants and three new individuals with de novo PCBP2 variants. Our findings add additional evidence for LEO1 as a risk gene for autism and intellectual disability. Furthermore, we prioritize PCBP2 as a candidate gene for NDD associated with motor and language delay. In summary, by leveraging de novo burden analysis studies, employing a stringent variant filtering pipeline, and engaging in targeted patient recruitment, our study contributes to the identification of novel genes implicated in NDDs.

Access to clinically indicated genetic tests for pediatric patients with Medicaid: Evidence from outpatient genetics clinics in Texas.

PURPOSE: Little is known about how Medicaid coverage policies affect access to genetic tests for pediatric patients. Building upon and extending a previous analysis of prior authorization requests (PARs), we describe expected coverage of genetic tests submitted to Texas Medicaid and the PAR and diagnostic outcomes of those tests. METHODS: We retrospectively reviewed genetic tests ordered at 3 pediatric outpatient genetics clinics in Texas. We compared Current Procedural Terminology (CPT) codes with the Texas Medicaid fee-for-service schedule (FFSS) to determine whether tests were expected to be covered by Medicaid. We assessed completion and diagnostic yield of commonly ordered tests. RESULTS: Among the 3388 total tests submitted to Texas Medicaid, 68.9% (n = 2336) used at least 1 CPT code that was not on the FFSS and 80.7% (n = 2735) received a favorable PAR outcome. Of the tests with a CPT code not on the FFSS, 60.0% (n = 1400) received a favorable PAR outcome and were completed and 20.5% (n = 287) were diagnostic. The diagnostic yield of all tests with a favorable PAR outcome that were completed was 18.7% (n = 380/2029). CONCLUSION: Most PARs submitted to Texas Medicaid used a CPT code for which reimbursement from Texas Medicaid was not guaranteed. The frequency with which clinically indicated genetic tests were not listed on the Texas Medicaid FFSS suggests misalignment between genetic testing needs and coverage policies. Our findings can inform updates to Medicaid policies to reduce coverage uncertainty and expand access to genetic tests with high diagnostic utility.

DNA methylation episignature in Gabriele-de Vries syndrome.

PURPOSE: Gabriele-de Vries syndrome (GADEVS) is a rare genetic disorder characterized by developmental delay and/or intellectual disability, hypotonia, feeding difficulties, and distinct facial features. To refine the phenotype and to better understand the molecular basis of the syndrome, we analyzed clinical data and performed genome-wide DNA methylation analysis of a series of individuals carrying a YY1 variant. METHODS: Clinical data were collected for 13 individuals not yet reported through an international call for collaboration. DNA was collected for 11 of these individuals and 2 previously reported individuals in an attempt to delineate a specific DNA methylation signature in GADEVS. RESULTS: Phenotype in most individuals overlapped with the previously described features. We described 1 individual with atypical phenotype, heterozygous for a missense variant in a domain usually not involved in individuals with YY1 pathogenic missense variations. We also described a specific peripheral blood DNA methylation profile associated with YY1 variants. CONCLUSION: We reported a distinct DNA methylation episignature in GADEVS. We expanded the clinical profile of GADEVS to include thin/sparse hair and cryptorchidism. We also highlighted the utility of DNA methylation episignature analysis for classification of variants of unknown clinical significance.

Outcomes of prior authorization requests for genetic testing in outpatient pediatric genetics clinics.

PURPOSE: Genetic testing is an important diagnostic tool in pediatric genetics clinics, yet many patients face barriers to testing. We describe the outcomes of prior authorization requests (PARs) for genetic tests, one indicator of patient access to clinically recommended testing, in pediatric genetics clinics. METHODS: We retrospectively reviewed PARs for genetic tests (n = 4,535) recommended for patients <18 years of age (n = 2,798) by pediatric medical geneticists at two children's hospitals in Texas, 2017-2018. We described PAR outcomes, accompanying diagnostic codes, and diagnostic yield. RESULTS: The majority (79.9%) of PARs received a favorable outcome. PARs submitted to public payers were more likely to receive a favorable outcome compared with private payers (85.5% vs. 70.3%, respectively; p < 0.001). No diagnostic codes were associated with higher likelihood of PAR approval for exome sequencing. Among the 2,685 tests approved and completed, 522 (19.4%) resulted in a diagnosis. CONCLUSION: Though there was a high PAR approval rate, our findings suggest that insurance coverage remains one barrier to genetic testing. When completed, genetic testing had a high yield in our sample. Further evidence of clinical utility and development of clinical practice guidelines may inform payer medical policy development and improve access to testing in the future.

Vertical transmission of a large calvarial ossification defect due to heterozygous variants of ALX4 and TWIST1.

ALX4 is a homeobox gene expressed in the mesenchyme of developing bone and is known to play an important role in the regulation of osteogenesis. Enlarged parietal foramina (EPF) is a phenotype of delayed intramembranous ossification of calvarial bones due to variants of ALX4. The contrasting phenotype of premature ossification of sutures is observed with heterozygous loss-of-function variants of TWIST1, which is an important regulator of osteoblast differentiation. Here, we describe an individual with a large cranium defect, with dominant transmission from the mother, both carrying disease causing heterozygous variants in ALX4 and TWIST1. The distinct phenotype of absent superior and posterior calvarium in the child and his mother was in sharp contrast to the other affected maternal relatives with a recognizable ALX4-related EPF phenotype. This report demonstrates comorbid disorders of Saethre-Chotzen syndrome and EPF in a mother and her child, resulting in severe skull defects reminiscent of calvarial abnormalities observed with bilallelic ALX4 variants. To our knowledge this is the first instance of ALX4 and TWIST1 variants acting synergistically to cause a unique phenotype influencing skull ossification.

Short stature and growth hormone deficiency in a subset of patients with Potocki-Lupski syndrome: Expanding the phenotype of PTLS.

Potocki-Lupski Syndrome (PTLS, MIM 610883), or duplication of chromosome 17p11.2, is a clinically recognizable condition characterized by infantile hypotonia, failure to thrive, developmental delay, intellectual disability, and congenital anomalies. Short stature, classified as greater than two standard deviations below the mean, has not previously been considered a major feature of PTLS. Retrospective chart review on a cohort of 37 individuals with PTLS was performed to investigate the etiology of short stature. Relevant data included anthropometric measurements, insulin growth factor-1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3), growth hormone (GH) stimulation testing, blood glucose levels, brain MRI, and bone age. Approximately 25% (9/37) of individuals with PTLS had short stature. Growth hormone deficiency (GHD) was definitively identified in two individuals. These two PTLS patients with growth hormone deficiency, as well as three others with short stature and no documented GHD, received growth hormone and obtained improvement in linear growth. One individual was identified to have pituitary abnormalities on MRI and had complications of hypoglycemia due to unrecognized GHD. Individuals with PTLS can benefit from undergoing evaluation for GHD should they present with short stature or hypoglycemia. Early identification of GHD could facilitate potential therapeutic benefit for individuals with PTLS, including linear growth, musculoskeletal, and in cases of hypoglycemia, potentially cognitive development as well.

Challenges in Prenatal Treatment with Dexamethasone.

Classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency causes elevated androgen levels, which can lead to virilization of female external genitalia. Prenatal dexamethasone treatment has been shown to be effective in preventing virilization of external genitalia when started prior to 7-9 weeks of gestation in females with classic CAH. However, CAH cannot be diagnosed prenatally until the end of the first trimester. Treating pregnant women with a fetus at risk of developing classic CAH exposes a significant proportion of fetuses unnecessarily, because only 1 in 8 would benefit from treatment. Consequently, prenatal dexamethasone treatment has been met with much controversy due to the potential adverse outcomes when exposed to high-dose steroids in utero. Here, we review the short- and long-term outcomes for fetuses and pregnant women exposed to dexamethasone treatment, the ethical considerations that must be taken into account, and current practice recommendations.