Genotype-phenotype correlations in patients with retinoblastoma and interstitial 13q deletions

Abstract

Patients with an interstitial 13q deletion that contains the RB1 gene show retinoblastoma and variable clinical features. Relationship between phenotypic expression and loss of specific neighboring genes are unresolved, yet. We obtained clinical, cytogenetic and molecular data in 63 patients with an interstitial 13q deletion involving RB1. Whole-genome array analysis or customized high-resolution array analysis for 13q14.11q14.3 was performed in 38 patients, and cytogenetic analysis was performed in 54 patients. Deletion sizes ranged between 4.2 kb and more than 33.43 Mb; breakpoints were non-recurrent. Sequence analysis of deletion junctions in five patients revealed microhomology and insertion of 2-34 base pairs suggestive of non-homologous end joining. Milder phenotypic expression of retinoblastoma was observed in patients with deletions larger than 1 Mb, which contained the MED4 gene. Clinical features were compared between patients with small (within 13q14), medium (within 13q12.3q21.2) and large (within 13q12q31.2) deletions. Patients with a small deletion can show macrocephaly, tall stature, obesity, motor and/or speech delay. Patients with a medium deletion show characteristic facial features, mild to moderate psychomotor delay, short stature and microcephaly. Patients with a large deletion have characteristic craniofacial dysmorphism, short stature, microcephaly, mild to severe psychomotor delay, hypotonia, constipation and feeding problems. Additional features included deafness, seizures and brain and heart anomalies. We found no correlation between clinical features and parental origin of the deletion. Our data suggest that hemizygous loss of NUFIP1 and PCDH8 may contribute to psychomotor delay, deletion of MTLR1 to microcephaly and loss of EDNRB to feeding difficulties and deafness.

Figure 1

Gene map of deletions in 38 patients and cases reported in the literature. Results of array CGH analysis were uploaded into UCSC Genome browser (on the basis of NCBI Build 36.1 March 2006, hg 18).

Figure 2

Results of breakpoint sequencing analysis in five patients. Sequence data show proximal and distal breakpoints. Sequence similarities to reference genomic sequence are indicated by vertical bars.

Figure 3

Correlation of retinoblastoma phenotype with deletion size. (a) Box plot: proportions of patients with a deletion involving the whole RB1 gene (both breakpoints out of RB1) or part of RB1 (one breakpoint in RB1). (b) One-factor analysis.

Figure 4

Facial phenotype. (a) Patients with a small deletion show a high forehead, a broad nose tip and a thin upper lip. (b) Patients with a medium deletion show a high forehead, deep-set eyes, a short nose in younger children, a small upper lip and often curly hair. (c) Patients with a large deletion show a round face in younger children, a long face in adult patients, a high forehead, a short nose, a long philtrum in older patients, a small upper lip and down-turned corners of the mouth. Patients 4, 8, 11, 20, 72, 76, 77 and 81 have hypertelorism, low-set ears and micrognathia.