Delineating the CCDC22-related Ritscher-Schinzel syndrome phenotype in the original family.

Pathogenic variants in CCDC22 were initially described in 2012 in a large Australian family with intellectual disability and were subsequently noted to cause a phenotype consistent with the previously described Ritscher-Schinzel syndrome (RSS). The phenotypes of the original family were not described in detail and remains limited phenotypic data reported in medical literature. We detail the phenotypes of the original family, including newly diagnosed family members. With these eight phenotypic descriptions, more than triple the number of individuals for whom detailed clinical information is available. In addition to typical facies, common phenotypic features included intellectual disability, congenital heart disease and posterior fossa malformations, postnatal short stature, ectodermal abnormalities, and digital anomalies as previously described. Spinal curvature and genital anomalies were seen in most patients, while gastrointestinal features and disturbed sleep were also recurrently seen. We propose a possible mechanism linking the familial variant to a diagnosis of sarcoidosis in one individual. Given the clinical and genetic heterogeneity of RSS, we suggest a dyadic naming convention.

Variable expressivity in a four-generation ACDMPV family with a non-coding hypermorphic SNV in trans to the frameshifting FOXF1 variant.

Heterozygous single nucleotide variants (SNVs) or copy-number variant deletions involving FOXF1 or its distant lung-specific enhancer on chromosome 16q24.1 have been identified in 80-90% of patients with Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV), a lethal neonatal lung developmental disorder. We describe a four-generation family with a deceased ACDMPV neonate, her sibling from the electively terminated pregnancy, healthy mother with a history of pulmonary arterial hypertension (PAH), an unaffected aunt, an aunt deceased due to findings consistent with ACDMPV, and a reportedly unaffected grandmother, all with the frameshifting variant c.881_902dup (p.Gly302Profs*46) in FOXF1, and a deceased great-grandmother with a history of PAH. Genome sequencing analyses in the proband's unaffected mother revealed a non-coding putative regulatory SNV rs560517434-A within the lung-specific distant FOXF1 enhancer in trans to the FOXF1 frameshift mutation. Functional testing of this variant using an in vitro luciferase reporter assay showed that it increased FOXF1 promoter activity 10-fold. Our studies further demonstrate that non-coding SNVs in the FOXF1 enhancer region can rescue the lethal ACDMPV phenotype and support the compound inheritance gene dosage model.

Clinical delineation, sex differences, and genotype-phenotype correlation in pathogenic KDM6A variants causing X-linked Kabuki syndrome type 2.

PURPOSE: The variant spectrum and the phenotype of X-linked Kabuki syndrome type 2 (KS2) are poorly understood. METHODS: Genetic and clinical details of new and published individuals with pathogenic KDM6A variants were compiled and analyzed. RESULTS: Sixty-one distinct pathogenic KDM6A variants (50 truncating, 11 missense) from 80 patients (34 males, 46 females) were identified. Missense variants clustered in the TRP 2, 3, 7 and Jmj-C domains. Truncating variants were significantly more likely to be de novo. Thirteen individuals had maternally inherited variants and one had a paternally inherited variant. Neonatal feeding difficulties, hypoglycemia, postnatal growth retardation, poor weight gain, motor delay, intellectual disability (ID), microcephaly, congenital heart anomalies, palate defects, renal malformations, strabismus, hearing loss, recurrent infections, hyperinsulinism, seizures, joint hypermobility, and gastroesophageal reflux were frequent clinical findings. Facial features of over a third of patients were not typical for KS. Males were significantly more likely to be born prematurely, have shorter stature, and severe developmental delay/ID. CONCLUSION: We expand the KDM6A variant spectrum and delineate the KS2 phenotype. We demonstrate that the variability of the KS2 phenotypic depends on sex and the variant type. We also highlight the overlaps and differences between the phenotypes of KS2 and KS1.

Feasibility of Ultra-Rapid Exome Sequencing in Critically Ill Infants and Children With Suspected Monogenic Conditions in the Australian Public Health Care System.

Importance: Widespread adoption of rapid genomic testing in pediatric critical care requires robust clinical and laboratory pathways that provide equitable and consistent service across health care systems. Objective: To prospectively evaluate the performance of a multicenter network for ultra-rapid genomic diagnosis in a public health care system. Design, Setting, and Participants: Descriptive feasibility study of critically ill pediatric patients with suspected monogenic conditions treated at 12 Australian hospitals between March 2018 and February 2019, with data collected to May 2019. A formal implementation strategy emphasizing communication and feedback, standardized processes, coordination, distributed leadership, and collective learning was used to facilitate adoption. Exposures: Ultra-rapid exome sequencing. Main Outcomes and Measures: The primary outcome was time from sample receipt to ultra-rapid exome sequencing report. The secondary outcomes were the molecular diagnostic yield, the change in clinical management after the ultra-rapid exome sequencing report, the time from hospital admission to the laboratory report, and the proportion of laboratory reports returned prior to death or hospital discharge. Results: The study population included 108 patients with a median age of 28 days (range, 0 days to 17 years); 34% were female; and 57% were from neonatal intensive care units, 33% were from pediatric intensive care units, and 9% were from other hospital wards. The mean time from sample receipt to ultra-rapid exome sequencing report was 3.3 days (95% CI, 3.2-3.5 days) and the median time was 3 days (range, 2-7 days). The mean time from hospital admission to ultra-rapid exome sequencing report was 17.5 days (95% CI, 14.6-21.1 days) and 93 reports (86%) were issued prior to death or hospital discharge. A molecular diagnosis was established in 55 patients (51%). Eleven diagnoses (20%) resulted from using the following approaches to augment standard exome sequencing analysis: mitochondrial genome sequencing analysis, exome sequencing-based copy number analysis, use of international databases to identify novel gene-disease associations, and additional phenotyping and RNA analysis. In 42 of 55 patients (76%) with a molecular diagnosis and 6 of 53 patients (11%) without a molecular diagnosis, the ultra-rapid exome sequencing result was considered as having influenced clinical management. Targeted treatments were initiated in 12 patients (11%), treatment was redirected toward palliative care in 14 patients (13%), and surveillance for specific complications was initiated in 19 patients (18%). Conclusions and Relevance: This study suggests feasibility of ultra-rapid genomic testing in critically ill pediatric patients with suspected monogenic conditions in the Australian public health care system. However, further research is needed to understand the clinical value of such testing, and the generalizability of the findings to other health care settings.