CELSR3 codes for a planar cell polarity protein. We describe twelve affected individuals from eleven independent families with bi-allelic variants in CELSR3. Affected individuals presented with an ...overlapping phenotypic spectrum comprising central nervous system (CNS) anomalies (7/12), combined CNS anomalies and congenital anomalies of the kidneys and urinary tract (CAKUT) (3/12) and CAKUT only (2/12). Computational simulation of the 3D protein structure suggests the position of the identified variants to be implicated in penetrance and phenotype expression. CELSR3 immunolocalization in human embryonic urinary tract and transient suppression and rescue experiments of Celsr3 in fluorescent zebrafish reporter lines further support an embryonic role of CELSR3 in CNS and urinary tract formation.
Cornelia de Lange syndrome (CdLS) is a well characterized developmental disorder. The genetic cause of CdLS is a mutation in one of five associated genes (NIPBL, SMC1A, SMC3, RAD21 and HDAC8) ...accounting for about 70 % of cases. To improve our current molecular diagnostic and to analyze some of CdLS candidate genes we developed and established a gene panel approach. Because recent data indicate a high frequency of mosaic NIPBL mutations that were not detected by conventional sequencing approaches of blood DNA, we started to collected buccal mucosa samples of our patients that were negative for mutations in the known CdLS genes. Here we report the identification of three mosaic NIPBL mutations by our high-coverage gene panel sequencing approach that were undetected by classical Sanger sequencing analysis of buccal mucosa DNA. All mutations were confirmed by the use of highly sensitive SNaPshot fragment analysis using DNA from buccal mucosa, urine and fibroblast samples. In blood samples we could not detect the respective mutation. Finally, in fibroblast samples from all three patients, Sanger sequencing could identify all the mutations. Thus, our study highlights the need for highly sensitive technologies in molecular diagnostic of CdLS to improve genetic diagnosis and counseling of patients and their families. This article is protected by copyright. All rights reserved.
To describe the clinical and genetic characteristics of a mother and her son presenting with two distinct and rare forms of retinal degeneration.
Investigations in both patients comprised spectral ...domain optical coherence tomography (SD-OCT), fundus autofluorescence imaging, non-contact biometry, ultrasonography, electroretinography (ERG) and analysis of the mutational status of the KCNV2 and MFRP genes in genomic DNA.
The clinical course and typical ERG pattern indicated a 'cone dystrophy with supernormal rod electroretinogram' in the proband, and SD-OCT demonstrated a subfoveal optical gap with loss of the inner segment/outer segment junction line. The proband was homozygous for a c.782C>A (p.Ala261Asp) mutation in KCNV2. Her son's axial length was shortened with refractive errors of +16.75 dioptres in the right and +14.0 dioptres in the left eye; ERG evidenced a rod-cone dystrophy, OCT showed central macular thickening with cystoid changes and ultrasonography revealed optic disc drusen. MFRP analysis disclosed a 1 bp deletion (c.498delC) that predicts a truncated protein.
Two distinct ocular phenotypes with pathogenic mutations in two different genes segregated in this family. The coexistence of two independent autosomal recessive disorders should be considered even when dealing with diseases that bear low carrier frequencies in the general population.
Mutations in the gene for 4-hydroxyphenylpyruvic acid dioxygenase (HPD) cause either autosomal recessive tyrosinemia type III or autosomal dominant hawkinsinuria. We report a 6-month-old Indian ...infant who is compound heterozygous for both alleles and who has hawkinsinuria but not tyrosinemia type III based on biochemical investigations. The HPD gene was directly sequenced in the proband and both parents. The mechanistic model of the enzymatic function was built using the known structure of rat HPD. We identified a novel hawkinsinuria mutation, Asn241Ser, and a known tyrosinemia type III mutation, Ile335Met, in trans configuration. The structural analysis of the active site revealed that the IIe335Met mutation is situated in the close vicinity of one of the two highly conserved Phe rings which stack with the phenol ring of the substrate. The Asn241Ser mutation is situated further away from the 4-hydroxyphenylpyruvate binding pocket. Assuming that Asn241Ser causes hawkinsinuria, we propose positioning the dioxygen molecule in the HPD-catalyzed reaction as a novel role for the Asn residue. The IIe335Met allele is equivalent to a null mutation while the Asn241Ser allele results in a partially active enzyme with an uncoupled turnover causing hawkinsinuria.
Apert syndrome is characterized by craniosynostosis, midfacial hypoplasia and symmetric cutaneous and bony syndactyly of the limbs. The skull is usually hyperacrobrachycephalic, whereas frank ...cloverleafing, as a clinically obvious trilobed skull deformity, is rarely seen in these patients. We report a rare case of Apert syndrome with cloverleaf skull deformity, prenatally diagnosed at 26weeks' gestation in which the sonographic features of a characteristic trilobed skull, abnormal biparietal diameter and head circumference, as well as malformations of the upper and lower extremities led to the diagnosis, confirmed by prenatal fibroblast growth factor receptor type 2 mutation analysis and fetal magnetic resonance imaging. The genetic evaluation revealed a p.P253R mutation in fibroblast growth factor receptor type 2 consisting in a transversion C>G at nucleotide 758. We discuss the relevant prenatal morphologic and genetic findings of this patient and review previously published cases. Our report demonstrates the feasibility of the prenatal diagnosis of Apert syndrome with cloverleaf skull using ultrasound, fetal magnetic resonance imaging and mutation analysis, and also highlights the importance of the biparietal diameter as an early predictor of growth restriction in severe craniosynostosis cases.
The aim of this prospective cardiological-linguistic study was to assess cause-specific and gender-specific differences in the reported symptoms and description of chest pain.
In patients ...hospitalized because of chest pain, location, radiation, quality of chest pain, pain precipitating and relieving factors, and additional symptoms were assessed. The cause of chest pain was assessed as either coronary or noncoronary. Patients' pain descriptions were taped for linguistic narrative analysis and transcribed according to ethnomethodological standards.
The cause of chest pain was assessed as coronary in 43 (18 females, 25 males, mean age 63 years) and noncoronary in 49 (30 females, 19 males, mean age 62 years) patients. Only few cause-related differences in the symptoms were found. In patients with a coronary cause, the location of chest pain was more often retrosternal (93% vs. 71%, p = 0.0078), in the right arm (23% vs. 6%, p = 0.0186), and less often in the back (28% vs. 51%, p = 0.0241) than in patients with a noncoronary cause of chest pain. Coronary patients more often had a pressing pain quality (81% vs. 61%, p = 0.034), less often pain precipitated by respiration (16% vs. 45%, p = 0.0032), and vertigo (21% vs. 43%, p = 0.0252) than noncoronary patients. The women were older than the men (mean age 65.6 vs. 59.0 years, p = 0.01). Women with a coronary cause more often had a gradual pain onset (78% vs. 48%, p = 0.0488) and relief by rest (78% vs. 40%, p = 0.0139) than men with a coronary cause. Linguistic analysis revealed that men presented themselves as interested in the cause of the chest pain, observing and describing pain concretely, whereas women presented themselves as prevailingly pain enduring, describing their pain diffusely.
Cause-related and gender-related differences in symptoms are too unspecific to distinguish between coronary and noncoronary causes. The strong gender differences in self-presentation and description of chest pain might be an explanation for underdiagnosis and undertreatment of women with coronary heart disease and should be considered when taking the clinical history of a female patient.
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