Pedigree of the S-family.

<p>The pedigree shows the 235 members of the S-family. The 76 members recruited in our study are highlighted. Nine members (S1, S2, S3, S4, S7, S8, S31, S41, S59) have WD. Generations were referred to by different colors: Gray for the 1^st and 2^nd; Black for the 3^rd; Pink for the 4^th; Blue for the 5^th and Red for the 6^th. <b>*</b> Refers to 2 men who were each married to 2 women.</p

Clinical, biochemical and genetic profile of WD patients in the S family.

a<p>Screening refers to genetic screening of the ATP7B gene exons' by PCR followed by sequencing; <b>^b</b>Few years later developed liver cirrhosis and portal hypertension;</p><p><b>Normal ranges of</b>: Serum ceruloplasmin: 0.15–0.60 g/; Serum Cu: 70–150 µg/dL; 24h urine Cu: 15–50 µg/24h; Bilirubin T/D: 0.2–1.2/0–0.5; ^blevel determined after 7 years of treatment; ^cUrinary Cu level while S41was on penicillamine; * c.2298_2299insC is referred to as 2299insC. DNA Mutation numbering is based on cDNA numbering where nucleotide +1 as the A of the ATG translation initiation codon, in the reference sequence # NM_000053 with the initiation codon aa codon +1.</p><p>Clinical, biochemical and genetic profile of WD patients in the S family.</p

Phenotype-Genotype Correlation in Wilson Disease in a Large Lebanese Family: Association of c.2299insC with Hepatic and of p. Ala1003Thr with Neurologic Phenotype

<div><p>Genotype phenotype correlations in Wilson disease (WD) are best established in homozygous patients or in compound heterozygous patients carrying the same set of mutations. We determined the clinical phenotype of patients with WD carrying the c.2298_2299insC in Exon 8 (c.2299insC) or the p. Ala1003Thr missense substitution in Exon 13 mutations in the homozygous or compound heterozygous state. We investigated 76 members of a single large Lebanese family. Their genotypes were determined, and clinical assessments were carried out for affected subjects. We also performed a literature search retrieving the phenotypes of patients carrying the same mutations of our patients in the homozygous or compound heterozygous state. There were 7 consanguineous marriages in this family and the prevalence of WD was 8.9% and of carriers of <i>ATP7B</i> mutation 44.7%. WD was confirmed in 9 out of 76 subjects. All 9 had the c.2299insC mutation, 5 homozygous and 4-compound heterozygous with p. Ala1003Thr. Six of our patients had hepatic, 2 had neurologic and 1 had asymptomatic phenotype. Based on our data and a literature review, clear phenotypes were reported for 38 patients worldwide carrying the c.2299insC mutation. About 53% of those have hepatic and 29% have neurologic phenotype. Furthermore, there were 10 compound heterozygous patients carrying the p. Ala1003Thr mutation. Among those, 80% having c.2299insC as the second mutation had hepatic phenotype, and all others had neurologic phenotype. We hereby report an association between the c.2299insC mutation and hepatic phenotype and between the p. Ala1003Thr mutation and neurologic phenotype.</p></div

Phenotypes of patients homozygous and/or heterozygous for the c. 2299insC reported in the literature.

<p>a. The identified c.2298–2299insC is referred to as c.2299insC.</p><p>b. The majority of asymptomatic patients in this study had transaminitis or hepatomegaly.</p><p>c. Asymptomatic transaminitis.</p><p>d. Asymptomatic fatty liver.</p><p>e. Unidentified or not reported.</p><p>Phenotypes of patients homozygous and/or heterozygous for the c. 2299insC reported in the literature.</p

Phenotypes of patients homozygous and/or heterozygous for the p. Ala1003Thr missense mutation reported in the literature.

<p>Phenotypes of patients homozygous and/or heterozygous for the p. Ala1003Thr missense mutation reported in the literature.</p

Dot blot image.

<p>A representative dot blot image of a membrane hybridized with normal and mutant probes of the identified exon 8 mutation. A dark spot resulting from hybridization with: Normal probe only, indicates a normal subject; Mutant probe only, indicates a homozygous subject; both normal and mutant probes indicate a carrier or heterozygous subject.</p