Carrier screening for Gaucher disease: lessons for low-penetrance, treatable diseases

Context  The aim of carrier screening is to prevent severe, untreatable genetic disease by identifying couples at risk before the birth of an affected child, and providing such couples with options for reproductive outcomes for affected pregnancies. Gaucher disease (GD) is an autosomal recessive storage disorder, relatively frequent in Ashkenazi Jews. Carrier screening for GD is controversial because common type 1 GD is often asymptomatic and effective treatment exists. However, screening is offered to Ashkenazi Jews worldwide and has been offered in Israel since 1995. Objective  To examine the scope and outcomes of nationwide GD screening. Design, Setting, and Participants  All Israeli genetic centers provided data on the number of individuals screened for GD, the number of carriers identified, the number of carrier couples identified, and the mutations identified in these couples between January 1, 1995, and March 31, 2003. Carrier couples were interviewed via telephone between January 21, 2003, and August 31, 2004, using a structured questionnaire for relevant outcome measures. Main Outcome Measures  Screening scope (number of testing centers, tested individuals, and carrier couples), screening process (type of pretest and posttest consultations), and screening outcomes (utilization of prenatal diagnosis and pregnancy terminations). Results  Between January 1, 1995, and March 31, 2003, 10 of 12 Israeli genetic centers (83.3%) offered carrier screening. Carrier frequency was 5.7%, and 83 carrier couples were identified among an estimated 28 893 individuals screened. There were 82 couples at risk for offspring with type 1 GD. Seventy of 82 couples (85%) were at risk for asymptomatic or mildly affected offspring and 12 of 82 couples (15%) were at risk for moderately affected offspring. At postscreening, 65 interviewed couples had 90 pregnancies, and prenatal diagnosis was performed in 68 pregnancies (76%), detecting 16 fetuses with GD (24%). Pregnancies were terminated in 2 of 13 fetuses (15%) predicted to be asymptomatic or mildly affected and 2 of 3 fetuses (67%) with predicted moderate disease. There were significantly fewer pregnancy terminations in couples who in addition to genetic counseling had medical counseling with a GD expert (1 of 13 [8%] vs 3 of 3 with no medical counseling [100%], P = .007). Conclusions  In this study of GD screening among Ashkenazi Jewish couples in Israel, most couples did not terminate affected pregnancies, although screening was associated with a few pregnancy terminations. The main possible benefit was providing couples with knowledge and control. The divergence of these outcomes from stated goals of screening programs is likely to confront carrier screening programs for low-penetrance diseases.      

Preimplantation genetic diagnosis (PGD) for nonsyndromic deafness by polar body and blastomere biopsy

Purpose  

Development of an efficient and reliable PGD protocol for nonsyndromic deafness, by polar body (PB) and blastomere PGD.     

Prevalence of glucocerebrosidase mutations in the Israeli Ashkenazi Jewish population

Gaucher disease is the most prevalent inherited disease among Ashkenazi Jews. It is very heterogeneous due to a large number of mutations within the glucocerebrosidase gene, whose impaired activity is the cause for this disease. Aiming at determining Gaucher carrier frequency among the Ashkenazi Jewish population in Israel, 1,208 individuals were molecularly diagnosed for six mutations known to occur among Ashkenazi Jewish Gaucher patients, using the newly developed Pronto™ Gaucher kit. The following mutations were tested: N370S, 84GG, IVS2+1, D409H, L444P, and V394L. Molecular testing of these mutations also allows identification of the recTL allele. The results indicated that Gaucher carrier frequency is 1:17 within the tested population. The prevalence of N370S carriers is 1:17.5. This implies that ˜1:1225 Ashkenazi Jews will be homozygous for the N370S mutation. Actually, in our study of 1,208 individuals one was found to be homozygous for the N370S mutation. The actual number of known Ashkenazi Jewish Gaucher patients with this genotype is much lower than that expected according to the frequency of the N370S mutation, suggesting a low penetrance of this mutation. Results of loading experiments in cells homozygous for the N370S mutation, as well as cells homozygous for the L444P and the D409H mutations, exemplified this phenomenon. Hum Mutat 12:240–244, 1998. © 1998 Wiley-Liss, Inc.     

A deleterious founder mutation in the BMPER gene causes diaphanospondylodysostosis (DSD)

Diaphonospondylodysostosis (DSD) is a rare, recessively inherited, lethal skeletal dysplasia, characterized by severe spinal ossification, segmentation defects, and renal cystic dysplasia with nephrogenic rests. We hereby present three affected individuals: two children and a fetus from two unrelated East Jerusalem Arab-Muslim families. Whereas most fetuses die in utero or perinatally, one of the children survived to 15 months. Homozygosity mapping in the two families demonstrated a single common 3.87 Mb region on chromosome 7, ruling out previously known spondylocostal/spondylothoracic dysostosis loci. The 15 protein coding genes in the region were prioritized, and some were sequenced. A single, novel deleterious mutation, Q104X, was detected in the bone morphogenetic protein-binding endothelial regulator protein (BMPER) gene, recently reported to be mutated in other DSD patients [Funari et al., 2010]. The novel mutation we identified is an ancestral founder allele, as evidenced by a shared 440 SNP haplotype, and its frequency in the general Arab population is estimated to be <1:123. Our findings confirm loss of BMPER function as a cause of axial versus appendicular skeletal defects, and suggest that less deleterious mutations may be involved in milder axial skeleton abnormalities.     

Hemolysis and bilirubin conjugation in association with UDP-glucuronosyltransferase 1A1 promoter polymorphism

Hemolysis may contribute to hyperbilirubinemia in Gilbert's syndrome. The authors examined blood carboxyhemoglobin corrected for inspired CO (COHbc) to index heme catabolism and serum conjugated bilirubin fractions to reflect bilirubin conjugation. Both parameters were related to UDP-glucuronosyltransferase 1A1 (UGT) promoter polymorphism, associated with Gilbert's syndrome, in term male newborns. COHbc was expressed as percentage of total hemoglobin, and total conjugated bilirubin (TCB) value as a percentage of serum total bilirubin (STB), (TCB/STB[%]). A production/conjugation index, COHbc/(TCB/STB[%]), represented bilirubin production divided by conjugation. UGT promoter genotype was designated according to the number of promoter TA insertions in each allele: 6/6, homozygous normal; 6/7, heterozygous; 7/7, homozygous variant. STB and COHbc values were higher in the 7/7 subgroup than the other counterparts (P <.01). The COHbc/(TCB/STB[%]) was higher in the 7/7 than either the 6/6 or 6/7 subsets (1.93 [1.31-2.88] vs. 0.85 [0.51-1.72] and 0.84 [0.53-1.87], respectively; P <.01). In conclusion, 7/7 UGT promoter polymorphism was associated with increased blood COHbc values (unexpected finding) as well as diminished serum total conjugated bilirubin ratios (expected finding). The increased hemolysis may contribute to the pathogenesis of increased STB values seen in Gilbert's syndrome, and exacerbate neonatal hyperbilirubinemia associated with the promoter polymorphism.