Inherited ichthyoses: molecular causes of the disease in Czech patients.

Inherited ichthyoses belong to a large and heterogeneous group of mendelian disorders of cornification, and can be distinguished by the quality and distribution of scaling and hyperkeratosis, by other dermatologic and extracutaneous involvement, and by inheritance. We present the genetic analysis results of probands with X-linked ichthyosis, autosomal recessive congenital ichthyosis, keratinopathic ichthyosis, and a patient with Netherton syndrome. Genetic diagnostics was complemented by in silico missense variant analysis based on 3D protein structures and commonly used prediction programs to compare the yields of these two approaches to each other. This analysis revealed various structural defects in proteins coded by mutated genes while no defects were associated with known polymorphisms. Two patients with pathogenic variants in the ABCA12 gene have a premature termination codon mutation on one allele and a silent variant on the second. The silent variants c.69G > A and c.4977G > A are localised in the last nucleotide of exon 1 and exon 32, respectively, and probably affect mRNA splicing. The phenotype of both patients is very severe, including a picture harlequin foetus after birth; later (at 3 and 6 years of age, respectively) ectropin, eclabion, generalised large polygonal scaling and erythema.

The 18q deletion syndrome and analysis of the critical region for orofacial cleft at 18q22.3.

INTRODUCTION: The 18q deletion syndrome (18q-) is a multiple-anomaly disorder associated with mental retardation, white matter anomalies in the brain, growth hormone deficiency, congenital aural atresia, orofacial cleft (OFC), and palate abnormalities. The aims of this study were to determine the frequency of different forms of OFC in 18q- individuals: cleft palate with or without cleft lip (CP/L), cleft lip (CL), and palate abnormalities. We also sought to map a potential critical region for OFC within chromosome 18q22.3 region. PATIENTS: The study presents an overview of selected 18q- individuals from 11 published reports and one presented poster. RESULTS: The frequency of CP/L and CL among 18q- individuals is about 25%; when high/arched palate cases are included, the frequency rises to about 43%. CONCLUSION: Orofacial abnormalities are characteristic features of 18q- syndrome patients and potential CP/L critical region could be assumed at 18q22.3 between markers D18S879 and D18S1141. In addition, gene deficient mouse models for Sall3 or Tshz1 genes, which are located at the 18q22.3 critical region, displayed palate abnormality phenotype.

Identification of 2.3-Mb gene locus for congenital aural atresia in 18q22.3 deletion: a case report analyzed by comparative genomic hybridization.

OBJECTIVE: 18q deletion syndrome is a multiple-anomaly mental retardation syndrome associated with congenital aural atresia. The purpose of this study was to determine the frequency of the congenital aural atresia phenotype in 18q deletion syndrome patients and to delineate a potential critical region for congenital aural atresia at the 18q22.3-18q23 region. STUDY DESIGN AND PATIENTS: The study describes one 18q deletion syndrome clinical report (Patient 15) with an overview of 19 other selected 18q deletion syndrome patients presenting congenital aural atresia from 18 published articles and one presented poster on 18q deletion syndrome. RESULTS: Our investigation, together with the results of published 18q deletion syndrome reports, shows that the average frequency of congenital aural atresia is approximately 52%. A combination of three 18q deletion syndrome probands defines a chromosomal deletion site for congenital aural atresia at 18q22.3-18q23 in the region between markers D18S489 and D18S554. These polymorphic markers outline a putative critical interval of approximately 2.3 Mb, including the genes ZNF407, ZADH2, SDCCAG33, ZNF516, FLJ44881, ZNF236, MBP-Golli, and GALR1. The haploinsufficiency of these genes is suggested to be a primary cause of congenital aural atresia phenotype in 18q deletion syndrome individuals. CONCLUSION: Congenital aural atresia is a relevant diagnostic clue and a major recognizable feature of 18q deletion syndrome. Early diagnosis of 18q deletion syndrome may enable application of hearing aids. Knockout studies on the congenital aural atresia mouse gene homolog may add further insight into the genes responsible for this condition.