Molecular cytogenetic characterization of a 4p15.1‐pter duplication and a 4q35.1‐qter deletion in a recombinant of chromosome 4 pericentric inversion

Abstract

To date, 10 cases of recombinant of chromosome 4 pericentric inversion involving sub-bands p14p15 and q35 have been described. We report on the first case analyzed using array-CGH in a female infant presenting psychomotor and growth retardation, facial anomalies, axial hypotonia, short neck, wide spaced nipples and cardiac defects. Conventional karyotype associated to FISH revealed a recombinant chromosome 4 with partial 4p duplication and 4q deletion derived from a paternal pericentric inversion. Array-CGH allowed us to precise rec4 breakpoints: the proposita carried a small 4.82-4.97 Mb 4q35.1 terminal deletion and a large 35.3-36.7 Mb 4p15.1 terminal duplication. Duplications of the distal 2/3 of short arm of chromosome 4 give rise to recognizable craniofacial features but no specific visceral malformation. A contrario small terminal 4q deletions are associated with cardiac defects. This case and review of literature suggest that two genes ArgBP2 and PDLIM3, located at 4q35.1 and both involved in cardiac and muscle development, could be responsible for cardiac defects observed in terminal 4q35.1 deletions.

Molecular cytogenetic characterization of a 2q35‐q37 duplication and a 4q35.1‐q35.2 deletion in two cousins: A genotype–phenotype analysis

“…One of the life‐threatening anomalies of 4q deletion syndrome is CHD [Strehle and Bantock, ]. It has been proposed that CHD could be associated with multiple 4q3 loci one within the 170–181 Mb interval containing two genes, TLL1 and HAND2 , involved in cardiac morphogenesis; the other more distal within the 4q35 band and containing two adiacent genes, PDLIM3 and SORBS2 , implicated in cardiac development [Maurin et al, ; Rashidi‐Nezhad et al, ; Vona et al, ]. Our patients, though heterozygous for the 4q35.1 band, are not affected by CHD, suggesting that haploinsufficiency of the candidate genes could have an incomplete penetrance.…”

“…With respect to 4q3 terminal deletion syndrome, patients with this condition display variable phenotypes that correlate with the extent and mapping of the rearranged region. Common clinical features include intellectual disability, a wide variety of head and facial abnormalities such as hypertelorism, malformed ears, cleft palate, short nose, congenital heart, and genitourinary defects [Maurin et al, ; Rashidi‐Nezhad et al, ; Strehle et al, ; Hemmat et al, ]. A number of cases of 4q deletion overlapping the 4q35.1‐q35.2 region have been reported: few of these have been isolated terminal 4q deletions, while the majority of patients also exhibited additional chromosomal rearrangements [Descartes et al, ; Tsai et al, ; Van Buggenhout et al, ; Cingoz et al, ; Vogt et al, ; Bendavid et al, ; Connel et al, ; Quadrelli et al, ; Bartholdi et al, ; Kaalund et al, ; Kitsiou‐Tzeli et al, ; Russel et al, ; Sensi et al, ; Maurin et al, ; Rossi et al, ; Chien et al, ; Markiewicz et al, ; Khalifa et al, ; Hemmat et al, ; Vona et al, ] (Fig.…”

Genotype-phenotype analysis of recombinant chromosome 4 syndrome: an array-CGH study and literature review

“…Including our patient, only 11 cases have been described to date [7,10-16,19]. Surprisingly, all cases have the same or very close breakpoints and all inherited the recombinant chromosome 4 from a parent who carried a pericentric inversion of chromosome 4.…”

“…In support of our findings, previous reports [20,21] indicated that cardiac defects are rarely observed in dup 4p patients whose duplication involves the same region affected in rec(4) patients. In addition, Maurin and colleagues [19] found the ArgBP2 and PDLIM3 genes in the 4q35.1 deleted region to be involved in cardiac muscle development. Similarly, urogenital abnormalities, which have rarely been reported in dup(4p) cases, have been consistently reported in 4q deletion syndrome and male rec(4) patients [11,15,19,22].…”

“…In addition, Maurin and colleagues [19] found the ArgBP2 and PDLIM3 genes in the 4q35.1 deleted region to be involved in cardiac muscle development. Similarly, urogenital abnormalities, which have rarely been reported in dup(4p) cases, have been consistently reported in 4q deletion syndrome and male rec(4) patients [11,15,19,22]. Therefore, we propose that the genes involved in male genital anomalies are located on 4q.…”