Unbalanced der(5)t(5;20) translocation associated with megalencephaly, perisylvian polymicrogyria, polydactyly and hydrocephalus

Abstract

The combination of megalencephaly, perisylvian polymicrogyria, polydactyly and hydrocephalus (MPPH) is a rare syndrome of unknown cause. We observed two first cousins affected by an MPPH-like phenotype with a submicroscopic chromosome 5q35 deletion as a result of an unbalanced der(5)t(5;20)(q35.2;q13.3) translocation, including the NSD1 Sotos syndrome locus. We describe the phenotype and the deletion breakpoints of the two MPPH-like patients and compare these with five unrelated MPPH and Sotos patients harboring a 5q35 microdeletion. Mapping of the breakpoints in the two cousins was performed by MLPA, FISH, high density SNP-arrays and Q-PCR for the 5q35 deletion and 20q13 duplication. The 5q35 deletion area of the two cousins almost completely overlaps with earlier described patients with an atypical Sotos microdeletion, except for the DRD1 gene. The five unrelated MPPH patients neither showed submicroscopic chromosomal aberrations nor DRD1 mutations. We reviewed the brain MRI of 10 Sotos patients and did not detect polymicrogyria in any of them. In our two cousins, the MPPH-like phenotype is probably caused by the contribution of genes on both chromosome 5q35 and 20q13. Some patients with MPPH may harbor a submicroscopic chromosomal aberration and therefore high-resolution array analysis should be part of the diagnostic workup.

Figure 1

Pedigree of family with Patient 1 (III-1) and 2 (III-2). (A) Pedigree, with two affected first cousins, Patient 1 and 2 (filled symbols), carrying an unbalanced 46,XXder(5)t(5;20)(q35.3;q13.3) translocation. Black dots indicate carriers of the balanced t(5;20)(q35.2;q13.3) translocation. (B) Patient 2 at the age of 3 months.

Figure 1

Pedigree of family with Patient 1 (III-1) and 2 (III-2). (A) Pedigree, with two affected first cousins, Patient 1 and 2 (filled symbols), carrying an unbalanced 46,XXder(5)t(5;20)(q35.3;q13.3) translocation. Black dots indicate carriers of the balanced t(5;20)(q35.2;q13.3) translocation. (B) Patient 2 at the age of 3 months.

Figure 2

Brain imaging. (A) T1 weighted axial brain MRI of patient 1 at the age of 2 years showing asymmetry of lateral ventricles with right-sided porencephalic cystic dilatation and perisylvian polymicrogyria (arrows). (B) Brain CT scan of Patient 2 at the age of 1.5 years showing hydrocephalus and bilateral wide sylvian fissures and cortical anomaly compatible with perisylvian polymicrogyria. (C) T1 weighted axial brain MRI of Patient 3 at the age of 3 years, showing prominent frontal lobes and no polymicrogyria. (D) T2 weighted axial brain MRI of Patient 8 at the age of 3 months, showing enlarged lateral ventricles and bilateral cortical polymicrogyria most prominent in perisylvian areas.

Figure 3

MLPA and FISH analysis on DNA of Patient III-1 and her mother II-2. (A and B) Ideograms, partial karyotype of chromosome 5 and 20 and the results of the MLPA P036B telomere analysis of (A) Patient 1 (III-1 in Fig 1) and (B) her mother (II-2 in Fig 1) are shown. (C) Fluorescence in situ hybridization experiments on metaphases obtained from cultured lymphocytes of the same Patient 1 (panels 1,2,4) and her mother (panel 3) hybridized with: C.1: 5pter (RP1-24H17) in red and 20qter (RP1-81F12) in green. C.2: 5pter (RP1-24H17 in red and 5q35 (NSD1 RP11-47L17) in green; C.3: 5p13.2 (RP11-253B9) and 5qter (RP-1240G13)in green and 20pter RP5-1061L1, 20qter (RP1-81F120 in red; C.4: 5p13.2 (RP11-253B9) in green and 5q35.3 (NSD1 RP1-118M12) in red. Note the unbalanced pattern in the patient (panels C1, C2 and C4) and the balanced pattern in the carrier of the balanced translocation (panel C3).

Figure 4

Overview of rearrangements with breakpoints in MPPH-like and Sotos patients. (A) view of SNP array data of chromosome 5 from Patient 1 with MPPH-like disease and Patient 3 with Sotos syndrome. (B) Scheme of 5q35 area with the deletions (in red) observed in Patient 1, 3 and published Patients COG025 and COG231 [Tatton-Brown et al., 2005b], and Patients 14 and 15 [Saugier-Veber et al., 2007]. Uninformative areas are indicated in grey. Genes and SNP locations in the breakpoint areas are indicated. (C) view of SNP array data and amplification (in green) of chromosome 20q13.3-qter from Patient 1.