Carrier frequency of autosomal‐recessive disorders in the Ashkenazi Jewish population: should the rationale for mutation choice for screening be reevaluated?

Fares, Fuad; Badarneh, Khader; Abosaleh, Mohamed; Harari-Shaham, Amalia; Diukman, Rony; David, Miriam

doi:10.1002/pd.1943

Cited by 36 publications

(22 citation statements)

References 30 publications

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“…The current recommendations by the Israel Society of Human Genetics suggest that genetic disorders with frequencies greater than 1 in 60 should be screened for, 4 indicating that WD and NSHL should be screened for in Korea. In addition, GSD Ia, PKU, CH and CLAH are serious childhood diseases.…”

Section: Discussionmentioning

confidence: 99%

“…1 Although the frequency of AR-MDs or XR-MRs is very low (1 in 10 000-100 000), the frequency of carriers is relatively high (1 in 30-300). 4 Moreover, patients have serious social and economic problems while carriers have no or subtle symptoms. However, according to recent research, carriers of mutations in certain genes that cause Mendelian disorders may have symptoms that emerge in old age.…”

Section: Introductionmentioning

confidence: 99%

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Estimation of carrier frequencies of six autosomal-recessive Mendelian disorders in the Korean population

Song

Lee

et al. 2011

J Hum Genet

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Although many studies have been performed to identify mutations in Korean patients with various autosomal-recessive Mendelian disorders (AR-MDs), little is known about the carrier frequencies of AR-MDs in the Korean population. Twenty common mutations from six AR-MDs, including Wilson disease (WD), non-syndromic hearing loss (NSHL), glycogen storage disease type Ia (GSD Ia), phenylketonuria (PKU), congenital hypothyroidism (CH), and congenital lipoid adrenal hyperplasia (CLAH) were selected to screen for based on previous studies. A total of 3057 Koreans were genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry followed by confirmation using the Sanger sequencing. We found 201 and 8 carriers with either one or two mutations in different genes, respectively, yielding a total carrier frequency of 1 in 15 (6.7%). Of the six AR-MDs, NSHL has the highest carrier frequency followed by WD, CH, CLAH, GSD Ia, and PKU. As carrier screening tests are becoming prevalent and the number of mutations known and tested is rising, a priori data on the carrier frequencies in different ethnic groups is mandatory to plan a population screening program and to estimate its efficiency. In light of this, the present results can be used as a basis to establish a screening policy for common AR-MRs in the Korean population.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Estimation of carrier frequencies of six autosomal-recessive Mendelian disorders in the Korean population

Song

Lee

et al. 2011

J Hum Genet

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“…Many cause a single amino acid change, resulting in reduced enzyme activity. The most common mutation in type 1 GD occurs at position c.1226 A>G, causing an N370S amino acid change [13], [14], [15]. Patients with this mutation exhibit variability in phenotype, ranging from asymptomatic individuals to those with severe visceral involvement or bone disease[16].…”

Section: Introductionmentioning

confidence: 99%

High Throughput Screening for Small Molecule Therapy for Gaucher Disease Using Patient Tissue as the Source of Mutant Glucocerebrosidase

et al. 2012

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Gaucher disease (GD), the most common lysosomal storage disorder, results from the inherited deficiency of the lysosomal enzyme glucocerebrosidase (GCase). Previously, wildtype GCase was used for high throughput screening (HTS) of large collections of compounds to identify small molecule chaperones that could be developed as new therapies for GD. However, the compounds identified from HTS usually showed reduced potency later in confirmatory cell-based assays. An alternate strategy is to perform HTS on mutant enzyme to identify different lead compounds, including those enhancing mutant enzyme activities. We developed a new screening assay using enzyme extract prepared from the spleen of a patient with Gaucher disease with genotype N370S/N370S. In tissue extracts, GCase is in a more native physiological environment, and is present with the native activator saposin C and other potential cofactors. Using this assay, we screened a library of 250,000 compounds and identified novel modulators of mutant GCase including 14 new lead inhibitors and 30 lead activators. The activities of some of the primary hits were confirmed in subsequent cell-based assays using patient-derived fibroblasts. These results suggest that primary screening assays using enzyme extracted from tissues is an alternative approach to identify high quality, physiologically relevant lead compounds for drug development.

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“…Homozygosity mapping has also been successful in identifying recessive risk variants for disorders showing Mendelian inheritance (Ekstein et al, 2004,Fares et al, 2008); and examples of successful mapping are also emerging for some complex psychiatric disorders, such as autism (Gamsiz et al, 2013,Lim et al, 2013,Yu et al, 2013). There is an increased interest in runs of homozygosity (ROH) given evidence of their association with increased risk for schizophrenia and other psychiatric disorders (Wang et al, 2010,Keller et al, 2012,Gamsiz et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Runs of homozygosity, copy number variation, and risk for depression and suicidal behavior in an Arab Bedouin kindred

Melhem

Hamdan

Klei

et al. 2017

Psychiatric Genetics

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Objectives Inbreeding increases the probability of homozygosity of deleterious alleles. Inbreeding and Runs of homozygosity (ROH) are associated with increased risk for disease phentoypes, including schizophrenia and other psychiatric disorders. Effects of inbreeding, ROH, homozygous deletions, and other copy number variations (CNVs) on risk for depression and suicide attempt were quantified in an Arab Bedouin Kindred. Methods We performed genetic analyses of 439 subjects from an Arab kindred with high rates of depression and suicidal behavior. We obtained complete ascertainment of suicide attempters and first-degree relatives of subjects who have attempted or died by suicide. Results We found extensive regions of ROH. On average, 5% of the genome is covered by ROH for these subjects, twofold higher than ROH rates for subjects from populations of European ancestry. Inbreeding and total length of ROH were not associated with risk for depression or attempt. For CNVs, an increased number of duplications >500 kb was associated with increased risk for attempt (OR=2.9, p=0.01; 95% CI 1.3, 6.6). While not significant after correction for multiple testing, risk for suicide attempt appears to increase with copy number for a CNV on chromosome 9p24.1. This possibility is intriguing because the CNV covers GLDC, which encodes glycine dehydrogenase that binds to glycine, a co-agonist at N-methyl-D-aspartate (NMDA) glutamate receptors and is involved in glutamatergic neurotransmission. Conclusions Our findings add to the growing evidence of genetic risk factors that act pleiotropically to increase risk for several neuropsychiatric disorders, including depression and suicide attempt, regardless of ancestry.

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Carrier frequency of autosomal‐recessive disorders in the Ashkenazi Jewish population: should the rationale for mutation choice for screening be reevaluated?

Cited by 36 publications

References 30 publications

Estimation of carrier frequencies of six autosomal-recessive Mendelian disorders in the Korean population

Estimation of carrier frequencies of six autosomal-recessive Mendelian disorders in the Korean population

High Throughput Screening for Small Molecule Therapy for Gaucher Disease Using Patient Tissue as the Source of Mutant Glucocerebrosidase

Runs of homozygosity, copy number variation, and risk for depression and suicidal behavior in an Arab Bedouin kindred

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