The filamin A gene
(FLNA)
on Xq28 encodes the filamin A protein. Mutation in
FLNA
causes a wide spectrum of disease including skeletal dysplasia, neuronal migration abnormality, cardiovascular ...malformation, intellectual disability and intestinal obstruction. Recently, childhood-onset interstitial lung disease associated with a range of
FLNA
mutations has been recognised and reported. We document our personal experience of this emerging disorder and compile a comprehensive overview of clinical features and molecular changes in all identifiable published cases. Reviewing the emerging dataset, we underline this unanticipated phenotypic consequence of pathogenic
FLNA
mutation-associated pulmonary disease.
Conclusion
: From the emerging data, we suggest that while reviewing complex cases with a sustained oxygen requirement against a clincial background of cardiac concerns or intestinal obstruction to have a high index of suspicion for
FLNA
related pathology and to instigate early MRI brain scan and
FLNA
mutation analysis.
What is Known:
• FLNA gene on Xq28 encodes the filamin A protein and mutation therein is associated with variable phenotypes depending on its nature of mutation.
• Loss-of-function mutation of filamin A is associated with X-linked inherited form of periventricular nodular heterotopia with or without epilepsy with most individuals affected being female. There is a recently recognised associated respiratory phenotype.
What is New:
• The respiratory phenotype in the form of childhood interstitial lung disease is a recently recognised clinical consequence of loss-of-function FLNA mutation.
• Rare male patients with loss-of-function FLNA mutation-associated lung disease with residual protein function can survive into infancy with a severe form of the phenotype.
The variant spectrum and the phenotype of X-linked Kabuki syndrome type 2 (KS2) are poorly understood.
Genetic and clinical details of new and published individuals with pathogenic KDM6A variants ...were compiled and analyzed.
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.
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.
The 2017 classification of Ehlers‐Danlos syndromes (EDS) identifies three types associated with causative variants in COL1A1/COL1A2 and distinct from osteogenesis imperfecta (OI). Previously, ...patients have been described with variable features of both disorders, and causative variants in COL1A1/COL1A2; but this phenotype has not been included in the current classification. Here, we expand and re‐define this OI/EDS overlap as a missing EDS type. Twenty‐one individuals from 13 families were reported, in whom COL1A1/COL1A2 variants were found after a suspicion of EDS. None of them could be classified as affected by OI or by any of the three recognized EDS variants associated with COL1A1/COL1A2. This phenotype is dominated by EDS‐related features. OI‐related features were limited to mildly reduced bone mass, occasional fractures and short stature. Eight COL1A1/COL1A2 variants were novel and five recurrent with a predominance of glycine substitutions affecting residues within the procollagen N‐proteinase cleavage site of α1(I) and α2(I) procollagens. Selected variants were investigated by biochemical, ultrastructural and immunofluorescence studies. The pattern of observed changes in the dermis and in vitro for selected variants was more typical of EDS rather than OI. Our findings indicate the existence of a wider recognizable spectrum associated with COL1A1/COL1A2.
COL1‐relatedoverlap disorder: a novel connective tissue disorder incorporating theosteogenesis imperfecta/Ehlers‐Danlos syndrome overlap.
Cystic fibrosis (CF) is the most common life-limiting autosomal recessive disease in the Republic of Ireland (ROI), with a previously quoted incidence of 1 in 1353 and carrier rate of 1 in 19. The ...National Newborn Screening (NBS) for CF was incorporated in July 2011 in the ROI. A cut-off point of the top 1% Immunoreactive Trypsinogen (IRT) was taken as an indication for 38 CFTR variant panel to maximise identification of affected CF cases and to minimise detection of carriers. All neonates from July 2011 to Dec 2017 with an elevated IRT on NBS were tested with 38 CFTR mutation panel and included. Clinical and laboratory database were analysed. In the first 6.5 years a total of 5,053 newborns (1.16% of total births) were screened with 38 CFTR panel. 170 CF affected cases, 320 unaffected carriers, 32 CF Screening Positive Inconclusive Diagnosis (CFSPID) were identified. There was one missed diagnosis. The most common disease-causing variant was c.1521_1523delCTT (p.(Phe508del)) followed by c.1652G>A (p.(Gly551Asp)). 95 out of 170 (55%) affected newborns were homozygous for c.1521_1523delCTT (p.(Phe08del)) and 25 (15%) carried at least one copy of c.1652G>A (p.(Gly551Asp)). Hence, 70% of affected newborns were eligible for CFTR modulator treatment. The NBS programme has identified almost triple the number of affected newborn with c.1652G>A (p.(Gly551Asp)) than previously quoted figures and identified less than 50% of carriers than predicted. The revised incidence and carrier frequency of CF in the ROI is 1 in 2570 and 1 in 25, respectively.
Intellectual disability (ID) is one of most frequent reasons for genetic consultation. The complex molecular anatomy of ID ranges from complete chromosomal imbalances to single nucleotide variant ...changes occurring de novo, with thousands of genes identified. This extreme genetic heterogeneity challenges the molecular diagnosis, which mostly requires a genomic approach. CXorf56 is largely uncharacterized and was recently proposed as a candidate ID gene based on findings in a single Dutch family. Here, we describe nine cases (six males and three females) from three unrelated families. Exome sequencing and combined database analyses, identified family-specific CXorf56 variants (NM_022101.3:c.498_503del, p.(Glu167_Glu168del) and c.303_304delCTinsACCC, p.(Phe101Leufs*20)) that segregated with the ID phenotype. These variants are presumably leading to loss-of-function, which is the proposed disease mechanism. Clinically, CXorf56-related disease is a slowly progressive neurological disorder. The phenotype is more severe in hemizygote males, but might also manifests in heterozygote females, which showed skewed X-inactivation patterns in blood. Male patients might present previously unreported neurological features such as epilepsy, abnormal gait, tremor, and clonus, which extends the clinical spectrum of the disorder. In conclusion, we confirm the causative role of variants in CXorf56 for an X-linked form of intellectual disability with additional neurological features. The gene should be considered for molecular diagnostics of patients with ID, specifically when family history is suggestive of X-linked inheritance. Further work is needed to understand the role of this gene in neurodevelopment and intellectual disability.
Colistin is an antimicrobial cationic peptide that belongs to the polymyxin family. Colistin was clinically used for the treatment of gram-negative infections but fell out of favour because of its ...significant side effects including neurotoxicity and nephrotoxicity. More recently, colistin has been regarded as one of the important options for nosocomial infections caused by multidrug resistant bacteria. Mechanisms of both the side effect onset of the drug and the side effect reduction are yet to be elucidated. In this study, we identified the specific binding protein of colistin using an affinity column chromatography. Colistin binds to the molecular chaperone HSP90. Although colistin slightly suppressed the chaperone activity of HSP90, there are no effects on the ATPase activity for a low concentration of colistin. Interestingly, colistin-induced aggregation of HSP90 via the N-domain. As for the cell viability of the SHSY5Y cell, the cell viability decreased to approximately 80% by the colistin 300 μM. However, the cell viability recovered to approximately 100% by adding ATP dosage. The same result was obtained by dot blot assay using anti-HSP90 antibody. Our results may help to understand the side effect mechanism of colistin.
•Patient-generated health data is key to understanding a patient's daily status.•A mobile app linked to a hospital information system via a QR code was developed.•The app collects data from patients’ ...mobiles and transfers these to the HIS.•Physicians use the health data efficiently for patient-centered medical care.
The collection of patient-generated health data (PGHD) is important for understanding a patient's daily status for efficient treatment. Mobile applications are effective for continuously collecting patient data, and it is desirable to promptly integrate such data into electronic medical records. However, most hospital information systems have limited connections with external mobile applications. Therefore, in this study, we developed a simple system that can collect data from patients with inflammatory bowel disease (IBD) and transfer the data to electronic medical records without a direct connection to a hospital information system.
We developed patient-facing mobile applications and physician-facing user-defined form templates for the hospital information system. The PGHD were transferred via QR codes using a two-way linkage. The persistence rates were measured and analyzed to clarify the factors affecting the continuous usage of the application.
A mobile application connected to a hospital information system was implemented and used in on-site operations. Among patients with IBD using this application, 84.6%–91.7% continued to use it over six months and 72.2%–84.5% continued for over one year. Particularly, patients who used the application during the first two visits tended to be significantly frequent users.
We developed a mobile application connected to a hospital information system using a QR code, which is a simple way to continuously collect data from patients and enables physicians to use the data efficiently for patient-centered medical care.
We report clinical and radiological features of a patient born with an isolated skull malformation of caput membranaceum and partial bicoronal craniosynostosis with a novel, de novo heterozygous ...missense variant in ZIC1 NM_003412.3:c.1183C>G, p.(Pro395Ala). Caput membranaceum, or boneless skull, is a rare manifestation of skull ossification defect. It can result from an isolated, enlarged parietal foramina or it can present as part of skeletal dysplasia syndromes associated with poor mineralization such as hypophosphatasia, osteogenesis imperfecta type II, and Saethre‐Chotzen syndrome. Their causative genes are well described. ZIC1, Zinc Finger protein of the cerebellum 1 (OMIM #600470) belongs to ZIC family genes, each encoding a Cys2 His2‐type zinc finger domain‐containing transcription factors. Recent studies have shown that pathogenic variants in ZIC1 have deleterious effect in developing human central nerves system and skull bone. ZIC1 related clinical conditions are reported and include cerebellum malformation, Dandy‐Walker malformation, spinal dysraphism, microcephaly, and craniosynostosis with associated intellectual disability. To‐date, there is no report of pathogenic variant in ZIC1 causing isolated caput membranaceum. Our observation adds to the clinical spectrum of ZIC1 related skull malformation.
We describe an X‐linked syndrome in 13 male patients from a single family with three generations affected. Patients presented prenatally or during the neonatal period with intrauterine growth ...retardation, ventriculomegaly, hydrocephalus, hypotonia, congenital heart defects, hypospadias, and severe neurodevelopmental delay. The disease is typically fatal during infancy, mainly due to sepsis (pneumonias). Female carriers are asymptomatic. We performed genome sequencing in four individuals and identified a unique candidate variant in the OTUD5 gene (NM_017602.3:c.598G > A, p.Glu200Lys). The variant cosegregated with the disease in 10 tested individuals. OTUD5 was considered as a candidate gene based on two previous missense variants detected in patients with intellectual disability. In conclusion, we define a syndrome associated with OTUD5 defects and add compelling evidence of genotype–phenotype association. This finding ended the long diagnostic odyssey of this family.
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