Comparative functional characterization of novel non-syndromic gene variant p.Gly45Arg and lethal syndromic variant p.Gly45Glu.

We characterized a novel missense variant, c.133G>A, p.Gly45Arg, and compared it with the only other variant at the same amino acid position of the connexin 26 protein (Cx26) reported to date: c.

Cystic fibrosis newborn screening programs: implications of the CFTR variant spectrum in nonwhite patients.

Purpose: Cystic fibrosis newborn screening (CFNBS) has been offered across the United States since 2010. However, as compared with white patients with CF, CFTR variant identification in nonwhite populations remains inequitable. Utilizing the recent characterization of the nonwhite CF variant spectrum, we examined the effectiveness of current CFNBS molecular panels in identifying affected nonwhite newborns.

The Spectrum of CFTR Variants in Nonwhite Cystic Fibrosis Patients: Implications for Molecular Diagnostic Testing.

Despite the implementation of cystic fibrosis (CF) newborn screening programs across the United States, the identification of CFTR gene variants in nonwhite populations compared with whites remains suboptimal. Our objective was to establish the spectrum of CFTR variants and their frequencies in CF patients in the United States with African, Native American, Asian, East Indian, or Middle Eastern backgrounds. By using direct DNA sequencing, we identified two CFTR variants in 89 of 140 affected nonwhite individuals with uncharacterized genotypes.

Assessment of epithelial sodium channel variants in nonwhite cystic fibrosis patients with non-diagnostic CFTR genotypes.

Purpose: Several lines of evidence suggest a role for the epithelial sodium channel (ENaC) in cystic fibrosis (CF). The purpose of our study was to assess the contribution of genetic variants in the ENaC subunits (α, β, γ) in nonwhite CF patients in whom CFTR molecular testing has been non-diagnostic.

Methods: Samples were obtained from patients who were nonwhite and whose molecular CFTR testing did not identify two mutations.

Mutation analysis of the SLC26A4, FOXI1 and KCNJ10 genes in individuals with congenital hearing loss.

Pendred syndrome (PDS) and DFNB4 comprise a phenotypic spectrum of sensorineural hearing loss disorders that typically result from biallelic mutations of the SLC26A4 gene. Although PDS and DFNB4 are recessively inherited, sequencing of the coding regions and splice sites of SLC26A4 in individuals suspected to be affected with these conditions often fails to identify two mutations. We investigated the potential contribution of large SLC26A4 deletions and duplications to sensorineural hearing loss (SNHL) by screening 107 probands with one known SLC26A4 mutation by Multiplex Ligation-dependent Probe Amplification (MLPA).

Acanthosis nigricans and hypochondroplasia in a child with a K650Q mutation in FGFR3.

Acanthosis nigricans has been described in several autosomal dominant skeletal dysplasia syndromes due to germline FGFR3 mutations, but rarely specifically in patients with hypochondroplasia. We report a child who presented with extensive acanthosis nigricans, short stature, and radiographic evidence of hypochondroplasia. Genetic analysis revealed a heterozygous K650Q mutation in FGFR3.

Identification of rare DNA variants in mitochondrial disorders with improved array-based sequencing.

A common goal in the discovery of rare functional DNA variants via medical resequencing is to incur a relatively lower proportion of false positive base-calls. We developed a novel statistical method for resequencing arrays (SRMA, sequence robust multi-array analysis) to increase the accuracy of detecting rare variants and reduce the costs in subsequent sequence verifications required in medical applications. SRMA includes single and multi-array analysis and accounts for technical variables as well as the possibility of both low- and high-frequency genomic variation.

Genotyping with a 198 mutation arrayed primer extension array for hereditary hearing loss: assessment of its diagnostic value for medical practice.

Molecular diagnostic testing of individuals with congenital sensorineural hearing loss typically begins with DNA sequencing of the GJB2 gene. If the cause of the hearing loss is not identified in GJB2, additional testing can be ordered. However, the step-wise analysis of several genes often results in a protracted diagnostic process.

Mitochondrial DNA analysis by multiplex denaturing high-performance liquid chromatography and selective sequencing in pediatric patients with cardiomyopathy.

Purpose: Mitochondrial DNA testing is typically performed by targeted mutation analysis only. We applied a more comprehensive approach to study the mitochondrial genome in 24 pediatric patients with idiopathic cardiomyopathy.

Methods: Patients in the cohort did not show overt multisystemic disease and were previously tested for mutations in a subset of structural genes associated with cardiomyopathy.

Multiplex ligation-dependent probe amplification identification of whole exon and single nucleotide deletions in the CFTR gene of Hispanic individuals with cystic fibrosis.

A disparity between Caucasian and Hispanic mutation detection for cystic fibrosis continues to exist, although the carrier frequency is only moderately lower in Hispanics. We aimed to identify exonic rearrangements that remained undetected by conventional methods. In seven of 32 cystic fibrosis-affected self-identified Hispanics for whom only one or no mutations were identified by extensive molecular testing, exon deletions appeared to be present with a multiplex ligation-dependent probe amplification (MLPA) assay.

Progressive cerebral vascular degeneration with mitochondrial encephalopathy.

MELAS (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes) is a maternally inherited disorder characterized by recurrent cerebral infarctions that do not conform to discreet vascular territories. Here we report on a patient who presented at 7 years of age with loss of consciousness and severe metabolic acidosis following vomiting and dehydration. She developed progressive sensorineural hearing loss, myopathy, ptosis, short stature, and mild developmental delays after normal early development.

Cystic fibrosis detection in high-risk Egyptian children and CFTR mutation analysis.

Background: Knowledge about Cystic Fibrosis (CF) in Egypt is very limited. The objective of this study was to screen for CF in Egyptian children with suggestive clinical features and to identify causative genetic mutations.

Methods: Sixty-one patients from the Chest Unit, Cairo University Children's Hospital, Egypt, were included.