Molecular cytogenetic analysis of de novo dup(5)(q35.2q35.3) and review of the literature of pure partial trisomy 5q

Abstract

An 11-year-old girl presented with the phenotype of microcephaly, moderate mental retardation, motor retardation, short stature, strabismus, brachydactyly, and facial dysmorphism. She had undergone surgery for inguinal hernias. Detailed examinations of the heart and other internal organs revealed normal findings. Her karyotype was 46,XX,dup(5)(q35.2q35.3) de novo. Molecular cytogenetic analysis showed a paternally derived 5q35.2 --> q35.3 direct duplication and led to a correlation between the particular genotype and phenotype. This is the first description of a direct duplication of 5q35.2 --> q35.3. Our case represents the smallest distal duplication of chromosome 5q that is not associated with congenital heart defects. Our case also represents the smallest distal duplication of chromosome 5q that is associated with short stature and microcephaly. Mutations or deletions of the NSD1 gene, mapped to 5q35.2 --> q35.3, has been known to cause Sotos syndrome with cerebral gigantism, macrocephaly, advanced bone age and overgrowth. Our case provides evidence that the gene dosage effect of the NSD1 gene causes a reversed phenotype of microcephaly and short stature.

A syndrome of short stature, microcephaly and speech delay is associated with duplications reciprocal to the common Sotos syndrome deletion

“…20 A patient with a smaller (520-650 kb) duplication within the Sotos syndrome critical region, also encompassing the NSD1 gene but not reciprocal to the common deletion (Figure 1e, top), had microcephaly and short stature in addition to mild facial dysmorphism. 21 This suggests that the gene dosage effect that seems to be responsible for this phenotype is limited to a region smaller than the 1.1 Mb minimum-duplicated fragment found in our patients, and that it is likely to involve the NSD1 gene.…”

“…A large duplication including this and adjacent regions, detected by fluorescence in situ hybridization (FISH), 20 and a small duplication contained within the region, detected by multiplex ligationdependent probe amplification (MLPA), 21 have been reported. However, the duplication reciprocal to the common deletion of the Sotos critical region predicted by nonallelic homologous recombination at the flanking LCRs has not been described to date, and its phenotypic consequences in humans are not known.…”

A rare case of a boy with de novo microduplication at 5q35.2q35.3 from central Brazil

“…Alteration in NSD1 dosage is responsible for Sotos syndrome, which has an inverted phenotype (Chen et al, 2006;Zhang et al, 2011). However, it is inappropriate to term the phenotype arising from the 5q35 microduplication as a "reversed SS" as there are other chromosomal imbalances that manifest as short stature and microcephaly, but lack the "reversed facial features" that are observed in patients harboring the duplicated 5q35.2q35.3 chromosomal region (Dikow et al, 2013).…”

Duplicación 5q34q35.3 que involucra el gen NSD1: región delimitada por microarreglos de hibridación genómica comparativa. A propósito de un caso

“…1,16 De acuerdo con nuestra revisión las características más frecuentes son: talla baja postnatal, retraso psicomotor, microcefalia, cara alargada, fisuras palpebrales cortas, nariz larga, filtrum plano, labio superior delgado, defectos en pabellones auriculares y craneosinostosis. [17][18][19][20][21] En la Figura 5 se muestra esquemáticamente los diferentes tamaños de duplicaciones de los casos previamente descritos y se hace una comparación con nuestra paciente. La duplicación de nuestra paciente es una de las más grandes informadas en la literatura (14Mb), siendo sólo superada por el reporte de Kariminejad et al 16 de 15Mb.…”