Familial transmission of 5p13.2 duplication due to maternal der(X)ins(X;5)

2015-04-06 00:01:35

European Journal of Medical Genetics; 6 April 2015; DOI: 10.1016/j.ejmg.2015.03.004

Lauren C. Walters-Sen, Kathy Windemuth, Katie Angione, Jenisha Nandhlal, Jeff M. Milunsky


Submicroscopic duplications of 5p13 have been recently reported in several cases, warranting the description of a new clinical entity (Chromosome 5p13 Duplication Syndrome; MIM 613174). These microduplications, while variable in size, all contain at least part of the NIPBL gene. Patients with duplications in this region present with intellectual disability/developmental delay (ID/DD) and dysmorphic facies. In addition, skeletal and brain abnormalities have been variably reported, as well as propensity for obesity in adulthood and hypotonia. We report a family with two affected sons and two affected daughters, each carrying a duplication at 5p13.2 encompassing the 3' portion of SLC1A3 and the 5' portion of NIPBL. Upon confirming the SNP microarray finding by FISH in the proband, it was discovered that the 5p13.2 duplication was located on the short arm of the X chromosome. Further FISH studies on the family demonstrated that all affected children and their mother carried a derivative X chromosome with insertion of material from 5p13.2 into the intermediate region of Xp [der(X)ins(X;5)(p2?2.1;p13.2p13.2)]. To our knowledge, this is the first report of an inherited duplication of 5p13.2 with multiple affected family members. This family underscores the need to confirm array findings by FISH, both in the proband and family members, to discern implications for pathogenicity and more accurately define the recurrence risk.


Partial duplications of the short arm of chromosome 5 have been associated with a wide spectrum of phenotypic consequences. Earlier studies of karyotypically visible duplications generated a
clinical picture that included developmental delay, seizures, brain abnormalities, heart defects, hypotonia, clubfeet, and respiratory difficulties. Dysmorphic features included macrocephaly, frontal bossing, micrognathia, flat nasal bridge, apparent hypertelorism, and dysplastic ears. The extent of these duplications ranged from the centromere of chromosome 5 to the telomere of
the short arm, with the majority containing multiple sub-bands. The modes of inheritance were variable; they included a recombinant due to a maternal paracentric inversion, a paternal three-way rearrangement on chromosome 5, a maternal insertion on chromosome 19, supernumerary marker chromosomes, a de novo inversion duplication, and a de novo interstitial duplication. Given the wide
range of phenotypic severity, these studies focused on major band 5p13 as the critical genomic region responsible for the phenotype.

Upon wide-spread introduction of microarray-CGH technologies into clinical laboratories, several patients with submicroscopic duplications at 5p13 have been reported. Oexle et al. described a de
novo 3.7 Mb duplication at 5p13.1-p13.2 which caused a phenotype nearly identical to the larger duplications detailed above. However, several of these duplications have been confined specifically to 5p13.2. The DECIPHER database includes two cases with ~520-530 kb 5p13.2 gains that both display autistic features and ocular dysmorphism (264548 and 270011). In addition, publications with more extensive phenotypic descriptions detail a milder phenotype consisting of developmental delay and dysmorphic facies similar to those seen in the larger duplication cases. In addition, other
abnormalities have been variably reported. These include skeletal anomalies, particularly of the hands; brain anomalies involving the corpus callosum; propensity for obesity in older children/
adults; and hypotonia. These duplications range in size from 0.25 Mb to 1.07 Mb; however, all contain at least a portion of the NIPBL gene (MIM: 608667). Of note, while inherited duplications
were observed with larger regions, each of the seven reported cases of 5p13.2 microduplication is a de novo direct duplication.

Here we report a family with four affected children with a 338-341 kb duplication at 5p13.2 that contains the 30 portion of SLC1A3 (MIM:600111) and the 5' portion of NIPBL, the result of an inherited derivative chromosome X containing the duplicated region of chromosome 5.

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Key Words

Microduplication | FISH | Microarray | Chromosome 5p | Familial