Quantification of Homozygosity in Consanguineous Individuals with Autosomal Recessive Disease

Woods, C. Geoffrey; Cox, James J.; Springell, Kelly; Hampshire, Daniel J.; Mohamed, Moin; McKibbin, Martin; Stern, Rowena; Raymond, F. Lucy; Sandford, Richard; Sharif, Saghira Malik; Karbani, G.; Ahmed, M.; Bond, Jacquelyn; Clayton, David; Inglehearn, Chris F.

doi:10.1086/503875

Cited by 223 publications

(198 citation statements)

References 19 publications

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“…In this study, the parents had inbreeding coefficients calculated as higher than expected for offspring of first cousins, whereas the average value for the offspring (19%) is greater than that predicted for double first cousins (12.5%). These values, although very high, are still within the range of estimates (5 -20%) reported for the offspring of first-cousin marriages of Pakistani and Arabian descent 17 and are in keeping with our knowledge that, historically, marriages within this family have been restricted to a small group of individuals from a small geographical region.…”

Section: Discussionsupporting

confidence: 89%

“…This data estimate an average tract size for offspring B6.58 ± 0.44 Mb, and average tract count 111 ± 5 (SEM). Assuming parity between cM and Mb, this would suggest a fivefold greater number of tracts that are, on average, a fifth of the size than that reported by Woods et al 17 Fa difference that may reflect more remote ancestry through additional ancestral inbreeding loops in this family.…”

Section: Discussionmentioning

confidence: 77%

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Homozygosity mapping in a family presenting with schizophrenia, epilepsy and hearing impairment

Knight

Maclean

Irfan³

et al. 2008

Eur J Hum Genet

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Homozygosity mapping within consanguineous families is a powerful method of localising genes for autosomal recessive disease. We investigated a family from Punjab, Pakistan, a region where consanguineous marriages are frequent. The parents have no detectable clinical disorders. However, five out of six children present with schizophrenia, epilepsy or hearing impairment either alone or in combination. This unusual phenotype in several offspring of first cousins is strongly suggestive of a rare, Mendelian recessive disorder. Two genome-wide scans initially using low-density microsatellites, and subsequently high-density SNP markers were used to map homozygous-by-descent regions in affected individuals. Candidate genes within these loci were subsequently screened for mutations. Homozygosity analysis and inbreeding coefficients were investigated to give an estimate of consanguinity. Two putative disease loci were mapped to 22q12.3 -q13.3 and 2p24.3. The candidate locus on chromosome 2p24 overlaps with a deafness locus, DFNB47, linked to autosomal recessive hearing impairment, while positive findings reported for affective psychosis and schizophrenia cluster in a region of 4-5 cM on 22q13.1 within our second candidate locus. Sequence analysis of three candidate genes (KCNF1 (2p); ATF4, CACNG2 (22q)) did not reveal any exonic mutations. Inbreeding coefficients calculated for each family member support a very high degree of ancestral and recent inbreeding. The screening of other candidate genes located within these newly identified disease intervals on Chr2p24.3 and 22q12.3-q13.3 may lead to the discovery of causative variants, and consequent disrupted molecular pathways associated with this rare phenotype.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 77%

Homozygosity mapping in a family presenting with schizophrenia, epilepsy and hearing impairment

Knight

Maclean

Irfan³

et al. 2008

Eur J Hum Genet

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“…As the two affected siblings were born out of a first-cousin marriage, we expected the diseasecausing mutation to be located in a homozygous interval. 3 To that end, genetic analyses started with the identification of these, followed by a panel-based next-generation sequencing approach and finally whole-genome sequencing.…”

Section: Introductionmentioning

confidence: 99%

Homozygosity mapping and whole-genome sequencing reveals a deep intronic PROM1 mutation causing cone–rod dystrophy by pseudoexon activation

et al. 2015

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Several genes have been implicated in the autosomal recessive form of cone-rod dystrophy (CRD), but the majority of cases remain unsolved. We identified a homozygous interval comprising two known genes associated with the autosomal recessive form of CRD, namely RAB28 and PROM1, in a consanguineous family with clinical evidence of CRD. Both genes proved to be mutation negative upon sequencing of exons and canonical splice sites but whole-genome sequencing revealed a private variant located deep in intron 18 of PROM1. In silico and functional analyses of this variant using minigenes as splicing reporters revealed the integration of a pseudoexon in the mutant transcript, thereby leading to a premature termination codon and presumably resulting in a functional null allele. This is the first report of a deep intronic variant that acts as a splicing mutation in PROM1. The detection of such variants escapes the exon-focused techniques typically used in genetic analyses. Sequencing the entire genomic regions of known disease genes might identify more causal mutations in the autosomal recessive form of CRD.

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“…14 DNA samples of the only available patients, I-2 and II-2, were analyzed, and homozygous regions 44.5 Mb were sought, as smaller homozygous regions were reported to occur at random, even in the offspring of nonconsanguineous couples. 15 The study was approved by the Hadassah Medical Center Ethical Review Committee.…”

Section: Methodsmentioning

confidence: 99%

Mutated NDUFS6 is the cause of fatal neonatal lactic acidemia in Caucasus Jews

Spiegel

Shaag

Mandel³

et al. 2009

Eur J Hum Genet

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NADH:ubiquinone oxidoreductase (complex I; EC 1.6.5.3), the largest respiratory chain complex is composed of 45 proteins and is located at the mitochondrial inner membrane. Defects in complex I are associated with energy generation disorders, of which the most severe is congenital lactic acidosis. We report on four infants from two unrelated families of Jewish Caucasus origin with fatal neonatal lactic acidemia due to isolated complex I deficiency. Whole genome homozygosity mapping, identified a 2.6 Mb region of identical haplotype in the affected babies. Sequence analysis of the nuclear gene encoding for the NDUFS6 mitochondrial complex I subunit located within this region identified the c.344G4A homozygous mutation resulting in substitution of a highly evolutionary conserved cysteine residue by tyrosine. This is the second report of NDUFS6 mutation in humans. Both reports describe three diverse homozygous mutations with variable consequential NDUFS6 protein defects that result in similar phenotype. Our study further emphasizes that NDUFS6 sequence should be analyzed in patients presenting with lethal neonatal lactic acidemia due to isolated complex I deficiency.

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Quantification of Homozygosity in Consanguineous Individuals with Autosomal Recessive Disease

Cited by 223 publications

References 19 publications

Homozygosity mapping in a family presenting with schizophrenia, epilepsy and hearing impairment

Homozygosity mapping in a family presenting with schizophrenia, epilepsy and hearing impairment

Homozygosity mapping and whole-genome sequencing reveals a deep intronic PROM1 mutation causing cone–rod dystrophy by pseudoexon activation

Mutated NDUFS6 is the cause of fatal neonatal lactic acidemia in Caucasus Jews

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