Clinical and molecular‐cytogenetic evaluation of a family with partial Jacobsen syndrome without thrombocytopenia caused by an ∼5 Mb deletion del(11)(q24.3)

Abstract

Clinical manifestations of Jacobsen syndrome (JBS) depend on the size of the 11qter deletion, which usually varies between approximately 7 and 20 Mb. Typical JBS features include developmental delay/mental retardation, short stature, congenital heart defects, thrombocytopenia, and characteristic dysmorphic facial features. We report on a family in which a 4-year-old girl as well as her mother and maternal uncle present with subtle features of JBS. Notably, neither thrombocytopenia nor congenital anomalies were detected in this family. Cytogenetic analyses revealed normal karyotypes. Using fluorescence in situ hybridization (FISH) and whole-genome oligonucleotide array CGH analyses, we identified an approximately 5 Mb deletion of the terminal part of chromosome 11q in all the three affected family members. The deletion breakpoint was mapped between 129,511,419 and 129,519,794 bp. This is the smallest deletion reported in a JBS patient. Interestingly, the FLI1 (friend leukemia virus integration 1) hematopoiesis factor gene located approximately 6.5 Mb from 11qter and usually deleted in patients with JBS, is intact. Our data support previous hypotheses that FLI1 haploinsufficiency is responsible for thrombocytopenia in patients with JBS.

SNP array and phenotype correlation shows that FLI1 deletion per se is not responsible for thrombocytopenia development in Jacobsen syndrome

“…Nevertheless, the deletions in both patients involved the most relevant gene for thrombocytopenia, the FLI1 gene (Friend leukemia virus integration 1), a transcription factor responsible for megakaryocytic maturation. Our data are therefore in conflict with a commonly accepted hypothesis that FLI1 gene hemizygous deletion contributes to thrombocytopenia in JBS patients [Raslova et al, 2004;Bernaciak et al, 2008]. Two other genes within the 11q terminal deletion are associated with hematopoiesis: ETS1 (v-ets erythroblastosis virus E26 oncogene homolog 1) and nuclear factor related to kappaB binding protein (NFRKB); additionally, junctional adhesion molecule 3 (JAM3) is expressed in platelets [Santoso et al, 2002].…”

“…Moreover, we are unaware of any reports of a male with FLI1 haploinsufficiency and normal platelet function and count. Of 12 patients (six males) who underwent detailed array-based deletion analysis, only two girls (including the present patient 1) presented with FLI1 deletion without thrombocytopenia [Bernaciak et al, 2008;Tyson et al, 2008;Manolakos et al, 2009;Ji et al, 2010;Basinko et al, 2011;Takahashi et al, 2011]. Similarly, a general male predominance for thrombocytopenia has been described in patients <2 years of age [Donato et al, 2009].…”

Application of custom-designed oligonucleotide array CGH in 145 patients with autistic spectrum disorders

“…If causative (with variable expressivity and incomplete penetrance), CHRNA7 duplication could be the most common CNV responsible for ASDs. SNX19 maps to the Jacobsen syndrome (JS, OMIM 147791) critical region 25 and is expressed in the brain. Ji et al 26 suggested that SNX19, in addition to THYN1, OPCML, NCAPD3, and NTM, may be responsible for DD/ID in patients with Jacobsen syndrome (JS).…”

De novo interstitial deletion in the long arm of chromosome 11: a case report

“…The 11q terminal deletion disorder or Jacobsen syndrome (JBS) is a rare genetic disorder associated with numerous dysmorphic features, and occurs in 1/100,000 live births with a female predominance of 2:1 (Sheth et al, 2014). Typical clinical characteristics of JBS include mental retardation, developmental delay, short stature, thrombocytopenia, and congenital heart defects (Bernaciak et al, 2008). Severity of clinical symptoms depends on the size of 11q23 deletions, which vary from 7 to 20 Mb, but can be as small as 2.9 Mb in some cases (Sheth et al, 2014).…”