Identification of a novel recessive RELN mutation using a homozygous balanced reciprocal translocation

Abstract

Two siblings from a consanguineous Egyptian marriage showed an identical phenotype of cortical lissencephaly with cerebellar hypoplasia, severe epilepsy, and mental retardation. Examination of karyotype revealed 46, t(7;12)(q22;p13)mat (7;12)(q22;p13)pat in both affected children, suggesting a homozygous reciprocal balanced translocation. Each healthy parent was a carrier of the balanced translocation in the heterozygous state, suggesting homozygous disruption of a gene involved in brain development. There were early spontaneous abortions in this family, as would be expected from transmission of an unbalanced chromosome. A disruption of RELN at 7q22.1 with absence of encoded protein was identified. This is the first demonstration that such rare homozygous translocations can be used to identify recessive disease gene mutations.

Heterozygous Reelin Mutations Cause Autosomal-Dominant Lateral Temporal Epilepsy

“…35 Three small consanguineous LCH-affected families in whom RELN mutations segregate with disease have been reported so far; heterozygote individuals in these families exhibited reduced levels of Reelin in their sera and were reported as clinically normal. 28,30 The apparent normal phenotype of these individuals is consistent with the relatively low penetrance of RELN mutations observed in this study and the possible occurrence of subtle epilepsy signs, not infrequent in ADLTE, which might remain undiagnosed in some individuals. Thus, as in other genetic epilepsy syndromes, 36 RELN mutations might result in different clinical phenotypes, depending on mode of inheritance: heterozygous mutations might cause ADLTE, and homozygous mutations might result in the more severe LCH.…”

“…27 Blood-serum Reelin, most of which is secreted from the liver, has been examined for the investigation of the effects of RELN mutations on extracellular Reelin levels in humans [28][29][30] and reeler mice. 27 In addition to the full-length protein (420 kDa), two smaller isoforms (160 and 310 kDa), resulting from enzymatic cleavage of the full-length protein, were detected by immunoblot (see schematic in Figure 2A).…”

Homozygosity for constitutional chromosomal rearrangements: a systematic review with reference to origin, ascertainment and phenotype

“…28 Reciprocal translocations Six reports of homozygosity for a reciprocal translocation were identified, involving five different translocations; t(Y;22); t(3;16); t(17;20); t(7;12) and t(10;11) ( Table 2; cases 11-16). 20,[31][32][33][34] In each instance, a consanguinous parental relationship existed, with each parent being heterozygous for the translocation. Furthermore, with the exception two siblings (cases [13][14], no cases involved the same translocation.…”

“…32,33 In cases 13 and 14, homozygosity for t(7;12) was discovered after evaluation and diagnosis of a rare neurodevelopmental disorder, lissencephaly with cerebellar hypoplasia. 32 The parents were phenotypically normal heterozygote first cousins, with a history of previous episodes of miscarriage. Subsequent molecular analyses showed homozygous inactivation of the RELN gene, which is located near the translocation breakpoint at 7q22 in both affected children.…”

“…Additional investigations of the mother showed reduced presence of RELN product consistent with reduced gene dosage because of heterozygosity for t(7;12). 32 In case 15, an infant presented with congenital sensorineural hearing loss, whose consanguinous parents reported a history of both successful pregnancy and previous spontaneous abortions. 33 Banding analysis of the family showed homozygosity for a t(10;11) in the affected child with both parents and four siblings each heterozygous.…”