Genetic heterogeneity in two consanguineous families segregating early onset retinal degeneration: The pitfalls of homozygosity mapping

Abstract

Retinitis pigmentosa is the most common form of hereditary retinal degeneration, with a worldwide prevalence of 1 in 4,000. At least 28 genes and loci have been implicated in nonsyndromic autosomal recessive retinitis pigmentosa. Here we report two extended and highly consanguineous families segregating early onset retinitis pigmentosa. Despite the consanguinity in both families, we found allelic heterogeneity in one of them, in which affected individuals were compound heterozygotes for two different mutations of the CRB1 gene. In the second family we found evidence for locus heterogeneity. A novel homozygous mutation of RDH12 was found in only 14 of 17 affected individuals in this family. Our data indicate that in the other affected individuals the disease is caused by a different gene/s. These findings demonstrate that while homozygosity mapping is an efficient tool for identification of the underlying mutated genes in inbred families, both locus and allelic heterogeneity may occur even within the same consanguineous family. These observations should be taken into account, especially when studying common and heterogeneous recessive genetic conditions.

Novel mutations in CRB1 and ABCA4 genes cause Leber congenital amaurosis and Stargardt disease in a Swedish family

“…Among 150 known CRB1 sequence variants, mutations in exon 7 are the most frequent (27%) and especially important for CRB1 function due to encoded laminin AG-like domain. 30,31 The c.5461-10T4C mutation was first reported by Maugeri et al, 32 although its function is still not resolved. The functional consequence of c.5461-10T4C was accessed in a study with the Exon Trapping System by Rivera et al, 33 who classified this nucleotide change as a rare sequence variant, as only correctly spliced exon was detected.…”

Map of autosomal recessive genetic disorders in Saudi Arabia: Concepts and future directions

“…Similarly, three different mutations in ECM1 were described in three Saudi families with the rare disorder of lipoid proteinosis (generalized thickening of skin, mucosae, and certain viscera) . Of interest, allelic heterogeneity has been reported in the same consanguineous kindred from other populations as an exceptionally rare event [Lezirovitz et al, 2008;Benayoun et al, 2009].…”

Identification of Mutations Causing Inherited Retinal Degenerations in the Israeli and Palestinian Populations Using Homozygosity Mapping

“…Fullfield ERG testing revealed low responses with a cone > rod pattern. Homozygosity mapping performed on five patients revealed many (3)(4)(5)(6)(7)(8)(9)(10)(11) homozygous regions per patient, which contained 9 to 13 candidate genes (Table 1). By combining homozygosity mapping data of family members, a single large shared homozygous region of 14.9 Mb was identified, including RDH12.…”

“…[3][4][5] On the other hand, one also should bear in mind that in some cases patients of consanguineous marriages are not homozygous for the disease-causing mutation, but rather are compound heterozygous and homozygosity mapping might be misleading in such families. [6][7][8] The Palestinian and Israeli populations include a large number of subpopulations (e.g., Jews, Arab-Muslims, ArabChristians, Bedouin, and Druze) with a relatively high frequency of consanguineous marriages and marriages between members of relatively isolated subpopulations. [9][10][11] The rates of consanguineous marriages are higher among Arab-Muslims, Druze, and Bedouins compared to Christian-Arabs 10 and Jews.…”