Microarray based analysis of an inherited terminal 3p26.3 deletion, containing only the CHL1 gene, from a normal father to his two affected children

Abstract

Background: terminal deletions of the distal portion of the short arm of chromosome 3 cause a rare contiguous gene disorder characterized by growth retardation, developmental delay, mental retardation, dysmorphisms, microcephaly and ptosis. The phenotype of individuals with deletions varies from normal to severe. It was suggested that a 1,5 Mb minimal terminal deletion including the two genes CRBN and CNTN4 is sufficient to cause the syndrome. In addition the CHL1 gene, mapping at 3p26.3 distally to CRBN and CNTN4, was proposed as candidate gene for a non specific mental retardation because of its high level of expression in the brain.

Methods and results: we describe two affected siblings in which array-CGH analysis disclosed an identical discontinuous terminal 3p26.3 deletion spanning less than 1 Mb. The deletion was transmitted from their normal father and included only the CHL1 gene. The two brothers present microcephaly, light mental retardation, learning and language difficulties but not the typical phenotype manifestations described in 3p- syndrome.

Conclusion: a terminal 3p26.3 deletion including only the CHL1 gene is a very rare finding previously reported only in one family. The phenotype of the affected individuals in the two families is very similar and the deletion has been inherited from an apparently normal parent. As already described for others recurrent syndromes with variable phenotype, these findings are challenging in genetic counselling because of an evident variable penetrance.

Figure 1

FISH and array CGH results. A) FISH with telomeric probes specific for the 3qter (red signals) and 3pter (green signal) regions. The arrow shows the absence of signal on the short arm of a chromosome 3. B) Array-CGH graphical overview of the 3p26.3 non contiguous terminal deletion. The region is deleted for the distal ~555.4 Kb from 62,075 Kb (A_18_P14035586) to 617,474 Kb (A_18_P14033572) and for the proximal ~199 kb from 758,905 Kb (A_16_P16103981) to 957,743 Kb (A_16_P16104360). Arrows indicate the non-deleted segment which spans from 626,187 Kb (A_16_P16103673) to 726,704 Kb (A_16_P36141085). From the left, the profiles refer to: first child, second child, normal mother and father. C) Custom image from UCSC Genome Browser showing an overview of the Refseq genes and CNVs content in the proximally deleted, normal and distally deleted regions.

Figure 2

Schematic representation of the previously reported 3p deletions analyzed by aCGH for which the extension of the deleted segment was reported. The black lines below the chromosomal 3p 26.3p25.3 region indicate the deletions whose references and extensions are indicated on the right.