Patient‐reported outcome measures (PROMs) are increasingly utilized as endpoints in clinical trials. The Short Form Health Survey‐12 (SF‐12v2) is a generic PROM for adults. We sought to evaluate the ...validity of SF‐12v2 in adults with osteogenesis imperfecta (OI). Physical and mental health‐related quality of life (HRQoL) were assessed in a large cohort of adults in a multicenter, observational, natural history study. Physical HRQoL scores were correlated with the Gillette Functional Assessment Questionnaire (GFAQ). We calculated sample sizes required in clinical trials with crossover and parallel‐group designs to detect clinically meaningful changes in physical HRQoL. Three hundred and two adults with OI types I, III, and IV were enrolled. Physical HRQoL scores in the study population were lower than population norms. Physical HRQoL scores moderately correlated with GFAQ for OI types I and IV. We found no correlations between mental and physical HRQoL. From a clinical trial readiness perspective, we show that SF‐12v2 reliably measures physical function in adults with OI and can be utilized in crossover trials to detect meaningful physical HRQoL changes with small sample sizes. This study shows that SF‐12v2 can be used to measure changes in physical HRQoL in response to interventions in OI.
Members of a paralogous gene family in which variation in one gene is known to cause disease are eight times more likely to also be associated with human disease. Recent studies have elucidated DHX30 ...and DDX3X as genes for which pathogenic variant alleles are involved in neurodevelopmental disorders. We hypothesized that variants in paralogous genes encoding members of the DExD/H-box RNA helicase superfamily might also underlie developmental delay and/or intellectual disability (DD and/or ID) disease phenotypes. Here we describe 15 unrelated individuals who have DD and/or ID, central nervous system (CNS) dysfunction, vertebral anomalies, and dysmorphic features and were found to have probably damaging variants in DExD/H-box RNA helicase genes. In addition, these individuals exhibit a variety of other tissue and organ system involvement including ocular, outer ear, hearing, cardiac, and kidney tissues. Five individuals with homozygous (one), compound-heterozygous (two), or de novo (two) missense variants in DHX37 were identified by exome sequencing. We identified ten total individuals with missense variants in three other DDX/DHX paralogs: DHX16 (four individuals), DDX54 (three individuals), and DHX34 (three individuals). Most identified variants are rare, predicted to be damaging, and occur at conserved amino acid residues. Taken together, these 15 individuals implicate the DExD/H-box helicases in both dominantly and recessively inherited neurodevelopmental phenotypes and highlight the potential for more than one disease mechanism underlying these disorders.
It has been estimated that 10–15% of people with Robinow syndrome (RS) show delayed development, but no studies have formally assessed developmental domains. The objective of this study is to provide ...the first description of cognitive, adaptive, and psychological functioning in RS. Thirteen participants (10 males) aged 4–51 years were seen for neuropsychological screening. Eight had autosomal‐dominant RS (DVL1, n = 5; WNT5A, n = 3), four had autosomal‐recessive RS (NXN, n = 2; ROR2, n = 2), and one had a mutation on an RS candidate gene (GPC4). Participants completed measures of intellectual, fine‐motor, adaptive, executive, and psychological functioning. Findings indicated generally average intellectual functioning and low‐average visuomotor skills. Adaptive functioning was average in autosomal‐recessive RS (RRS) but low average in autosomal‐dominant RS (DRS). Parent‐report indicated executive dysfunction and attention problems in 4/8 children, 3/4 of whom had a DVL1 variant; adult self‐report did not indicate similar difficulties. Learning disabilities were also reported in 4/8 individuals with DRS, 3/4 of whom had a DVL1 variant. Peer problems were reported for a majority of participants, many of whom also reported emotional concerns. Altogether, the findings indicate average neurocognitive functioning in RRS. In contrast, DRS, especially DVL1 pathogenic alleles, may confer specific risk for neurodevelopmental disability.
Pathogenic autosomal recessive variants in CAD, encoding the multienzymatic protein initiating pyrimidine de novo biosynthesis, cause a severe inborn metabolic disorder treatable with a dietary ...supplement of uridine. This condition is difficult to diagnose given the large size of CAD with over 1000 missense variants and the nonspecific clinical presentation. We aimed to develop a reliable and discerning assay to assess the pathogenicity of CAD variants and to select affected individuals that might benefit from uridine therapy.
Using CRISPR/Cas9, we generated a human CAD-knockout cell line that requires uridine supplements for survival. Transient transfection of the knockout cells with recombinant CAD restores growth in absence of uridine. This system determines missense variants that inactivate CAD and do not rescue the growth phenotype.
We identified 25 individuals with biallelic variants in CAD and a phenotype consistent with a CAD deficit. We used the CAD-knockout complementation assay to test a total of 34 variants, identifying 16 as deleterious for CAD activity. Combination of these pathogenic variants confirmed 11 subjects with a CAD deficit, for whom we describe the clinical phenotype.
We designed a cell-based assay to test the pathogenicity of CAD variants, identifying 11 CAD-deficient individuals who could benefit from uridine therapy.
Genomic instability is a feature of the human Xp22.31 region wherein deletions are associated with X-linked ichthyosis, mental retardation and attention deficit hyperactivity disorder. A putative ...homologous recombination hotspot motif is enriched in low copy repeats that mediate recurrent deletion at this locus. To date, few efforts have focused on copy number gain at Xp22.31. However, clinical testing revealed a high incidence of duplication of Xp22.31 in subjects ascertained and referred with neurobehavioral phenotypes. We systematically studied 61 unrelated subjects with rearrangements revealing gain in copy number, using multiple molecular assays. We detected not only the anticipated recurrent and simple nonrecurrent duplications, but also unexpectedly identified recurrent triplications and other complex rearrangements. Breakpoint analyses enabled us to surmise the mechanisms for many of these rearrangements. The clinical significance of the recurrent duplications and triplications were assessed using different approaches. We cannot find any evidence to support pathogenicity of the Xp22.31 duplication. However, our data suggest that the Xp22.31 duplication may serve as a risk factor for abnormal phenotypes. Our findings highlight the need for more robust Xp22.31 triplication detection in that such further gain may be more penetrant than the duplications. Our findings reveal the distribution of different mechanisms for genomic duplication rearrangements at a given locus, and provide insights into aspects of strand exchange events between paralogous sequences in the human genome.
Glypicans are a family of cell-surface heparan sulfate proteoglycans that regulate growth-factor signaling during development and are thought to play a role in the regulation of morphogenesis. ...Whole-exome sequencing of the Australian family that defined Keipert syndrome (nasodigitoacoustic syndrome) identified a hemizygous truncating variant in the gene encoding glypican 4 (GPC4). This variant, located in the final exon of GPC4, results in premature termination of the protein 51 amino acid residues prior to the stop codon, and in concomitant loss of functionally important N-linked glycosylation (Asn514) and glycosylphosphatidylinositol (GPI) anchor (Ser529) sites. We subsequently identified seven affected males from five additional kindreds with novel and predicted pathogenic variants in GPC4. Segregation analysis and X-inactivation studies in carrier females provided supportive evidence that the GPC4 variants caused the condition. Furthermore, functional studies of recombinant protein suggested that the truncated proteins p.Gln506∗ and p.Glu496∗ were less stable than the wild type. Clinical features of Keipert syndrome included a prominent forehead, a flat midface, hypertelorism, a broad nose, downturned corners of mouth, and digital abnormalities, whereas cognitive impairment and deafness were variable features. Studies of Gpc4 knockout mice showed evidence of the two primary features of Keipert syndrome: craniofacial abnormalities and digital abnormalities. Phylogenetic analysis demonstrated that GPC4 is most closely related to GPC6, which is associated with a bone dysplasia that has a phenotypic overlap with Keipert syndrome. Overall, we have shown that pathogenic variants in GPC4 cause a loss of function that results in Keipert syndrome, making GPC4 the third human glypican to be linked to a genetic syndrome.
In this report, we describe two cousins with cognitive impairment, growth failure, skeletal abnormalities, and distinctive facial features. Genome sequencing failed to identify variants in known ...disease‐associated genes explaining the phenotype. Extended comprehensive analysis of the two affected cousins' genomes, however, revealed that both share the homozygous nonsense variant c.178G>T (p.Glu60*) in the VPS26C gene. This gene encodes VPS26C, a member of the retriever integral membrane protein recycling pathway. The potential vital biological role of VPS26C, the nature of the variant which is predicted to result in loss‐of‐function, expression studies revealing significant reduction in the mutant transcript, and the co‐segregation of the homozygous variant with the phenotype in two affected individuals all support that VPS26C is a novel gene associated with a previously unrecognized syndrome characterized by neurodevelopmental deficits, growth failure, skeletal abnormalities, and distinctive facial features.
Genomic sequencing offers an untargeted, data-driven approach to genetic diagnosis; however, variants of uncertain significance often hinder the diagnostic process. The discovery of rare genomic ...variants without previously known functional evidence of pathogenicity often results in variants being overlooked as potentially causative, particularly in individuals with undifferentiated phenotypes. Consequently, many neurometabolic conditions, including those in the GABA (gamma-aminobutyric acid) catabolism pathway, are underdiagnosed. Succinic semialdehyde dehydrogenase deficiency (SSADHD, OMIM #271980) is a neurometabolic disorder in the GABA catabolism pathway. The disorder is due to bi-allelic pathogenic variants in ALDH5A1 and is usually characterized by moderate-to-severe developmental delays, hypotonia, intellectual disability, ataxia, seizures, hyperkinetic behavior, aggression, psychiatric disorders, and sleep disturbances. In this study, we utilized an integrated approach to diagnosis of SSADHD by examining molecular, clinical, and metabolomic data from a single large commercial laboratory. Our analysis led to the identification of 16 patients with likely SSADHD along with three novel variants. We also showed that patients with this disorder have a clear metabolomic signature that, along with molecular and clinical findings, may allow for more rapid and efficient diagnosis. We further surveyed all available pathogenic/likely pathogenic variants and used this information to estimate the global prevalence of this disease. Taken together, our comprehensive analysis allows for a global approach to the diagnosis of SSADHD and provides a pathway to improved diagnosis and potential incorporation into newborn screening programs. Furthermore, early diagnosis facilitates referral to genetic counseling, family support, and access to targeted treatments–taken together, these provide the best outcomes for individuals living with either GABA-TD or SSADHD, as well as other rare conditions.
Introduction
Cranio‐cervical anomalies are significant complications of osteogenesis imperfecta (OI), a rare bone fragility disorder that is usually caused by mutations in collagen type I encoding ...genes.
Objective
To assess cranio‐cervical anomalies and associated clinical findings in patients with moderate‐to‐severe OI using 3D cone beam computed tomography (CBCT) scans.
Methods
Cross‐sectional analysis of CBCT scans in 52 individuals with OI (age 10–37 years; 32 females) and 40 healthy controls (age 10–32 years; 26 females). Individuals with a diagnosis of OI type III (severe, n = 11), type IV (moderate, n = 33) and non‐collagen OI (n = 8) were recruited through the Brittle Bone Disorders Consortium. Controls were recruited through the orthodontic clinic of the University of Missouri‐Kansas City (UMKC).
Results
OI and control groups were similar in mean age (OI: 18.4 SD: 7.2 years, controls: 18.1 SD: 6.3 years). The cranial base angle was increased in the OI group (OI: mean 148.6° SD: 19.3, controls: mean 130.4° SD: 5.7, P = .001), indicating a flatter cranial base. Protrusion of the odontoid process into the foramen magnum (n = 7, 14%) and abnormally located odontoid process (n = 19, 37%) were observed in the OI group but not in controls. Low stature, expressed as height z‐score (P = .01), presence of DI (P = .04) and being male (P = .04) were strong predictors of platybasia, whereas height z‐score (P = .049) alone was found as positive predictor for basilar impression as per the Chamberlain measurement.
Conclusion
The severity of the phenotype in OI, as expressed by the height z‐score, correlates with the severity of cranial base anomalies such as platybasia and basilar impression in moderate‐to‐severe OI. Screening for cranial base anomalies is advisable in individuals with moderate‐to‐severe OI, with special regards to the individuals with a shorter stature and DI.
WNT signaling promotes the reprogramming of somatic cells to an induced pluripotent state. We provide genetic evidence that WNT signaling is a requisite step during the induction of pluripotency. ...Fibroblasts from individuals with focal dermal hypoplasia (FDH), a rare genetic syndrome caused by mutations in the essential WNT processing enzyme PORCN, fail to reprogram with standard methods. This blockade in reprogramming is overcome by ectopic WNT signaling and PORCN overexpression, thus demonstrating that WNT signaling is essential for reprogramming. The rescue of reprogramming is critically dependent on the level of WNT signaling: steady baseline activation of the WNT pathway yields karyotypically normal iPSCs, whereas daily stimulation with Wnt3a produces FDH-iPSCs with severely abnormal karyotypes. Therefore, although WNT signaling is required for cellular reprogramming, inappropriate activation of WNT signaling induces chromosomal instability, highlighting the precarious nature of ectopic WNT activation and its tight relationship with oncogenic transformation.
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