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Microdeletions in 9q33.3-q34.11 in five patients with intellectual disability, microcephaly, and seizures of incomplete penetrance: is STXBP1 not the only causative gene?

Ehret JK, Engels H, Cremer K, Becker J, Zimmermann JP, Wohlleber E, Grasshoff U, Rossier E, Bonin M, Mangold E, Bevot A, Schön S, Heilmann-Heimbach S, Dennert N, Mathieu-Dramard M, Lacaze E, Plessis G, de Broca A, Jedraszak G, Röthlisberger B, Miny P, Filges I, Dufke A, Andrieux J, Lee JA, Zink AM - Mol Cytogenet (2015)

Bottom Line: The smallest region of overlap (SRO) of these deletions in 9q33.3 does not encompass STXBP1, but includes two genes that have not been previously associated with disease, RALGPS1 and GARNL3.Gene expression analyses in our patients demonstrated significantly reduced expression levels of GARNL3, RALGPS1 and STXBP1 only in patients with deletions of the corresponding genes.Thus, reduced expression of STXBP1 was ruled out as a cause for seizures in our patient whose deletion did not encompass STXBP1.

View Article: PubMed Central - PubMed

Affiliation: Institute of Human Genetics, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.

ABSTRACT

Background: Most microdeletions involving chromosome sub-bands 9q33.3-9q34.11 to this point have been detected by analyses focused on STXBP1, a gene known to cause early infantile epileptic encephalopathy 4 and other seizure phenotypes. Loss-of-function mutations of STXBP1 have also been identified in some patients with intellectual disability without epilepsy. Consequently, STXBP1 is widely assumed to be the gene causing both seizures and intellectual disability in patients with 9q33.3-q34.11 microdeletions.

Results: We report five patients with overlapping microdeletions of chromosome 9q33.3-q34.11, four of them previously unreported. Their common clinical features include intellectual disability, psychomotor developmental delay with delayed or absent speech, muscular hypotonia, and strabismus. Microcephaly and short stature are each present in four of the patients. Two of the patients had seizures. De novo deletions range from 1.23 to 4.13 Mb, whereas the smallest deletion of 432 kb in patient 3 was inherited from her mother who is reported to have mild intellectual disability. The smallest region of overlap (SRO) of these deletions in 9q33.3 does not encompass STXBP1, but includes two genes that have not been previously associated with disease, RALGPS1 and GARNL3. Sequencing of the two SRO genes RALGPS1 and GARNL3 in at least 156 unrelated patients with mild to severe idiopathic intellectual disability detected no causative mutations. Gene expression analyses in our patients demonstrated significantly reduced expression levels of GARNL3, RALGPS1 and STXBP1 only in patients with deletions of the corresponding genes. Thus, reduced expression of STXBP1 was ruled out as a cause for seizures in our patient whose deletion did not encompass STXBP1.

Conclusions: We suggest that microdeletions of this region on chromosome 9q cause a clinical spectrum including intellectual disability, developmental delay especially concerning speech, microcephaly, short stature, mild dysmorphisms, strabismus, and seizures of incomplete penetrance, and may constitute a new contiguous gene deletion syndrome which cannot completely be explained by deletion of STXBP1.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of the microdeletions. Red bars: Microdeletions of patients 1 through 5 are presented. Grey bars: previously published microdeletions. Lower panel: detail with smallest region of overlap (SRO, dashed lines, red box) and RefSeq genes with black arrows showing direction of transcription (green: genes analyzed by expression studies)
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Fig2: Schematic representation of the microdeletions. Red bars: Microdeletions of patients 1 through 5 are presented. Grey bars: previously published microdeletions. Lower panel: detail with smallest region of overlap (SRO, dashed lines, red box) and RefSeq genes with black arrows showing direction of transcription (green: genes analyzed by expression studies)

Mentions: In patients 1, 2, 4 and 5, de novo deletions in 9q33.3-q34.11 ranging from 1.23 to 4.13 Mb were detected using various array platforms (Table 1, Fig. 2). Interestingly, the smallest deletion was detected in patient 3, whose 432-kb deletion was inherited from her mother who is reported to have mild ID. The smallest region of overlap (SRO) is defined by the distal boundary of the deletion in patient 3 and the proximal deletion boundary in patient 5, and includes only two RefSeq genes, RALGPS1 and GARNL3. In patients 1, 2, 3 and 4, ANGPTL2 is also deleted. Importantly, the SRO does not include the STXBP1 gene in 9q34.11 (Fig. 2). No additional de novo CNVs or CNVs in known copy number-sensitive regions have been detected.Table 1


Microdeletions in 9q33.3-q34.11 in five patients with intellectual disability, microcephaly, and seizures of incomplete penetrance: is STXBP1 not the only causative gene?

Ehret JK, Engels H, Cremer K, Becker J, Zimmermann JP, Wohlleber E, Grasshoff U, Rossier E, Bonin M, Mangold E, Bevot A, Schön S, Heilmann-Heimbach S, Dennert N, Mathieu-Dramard M, Lacaze E, Plessis G, de Broca A, Jedraszak G, Röthlisberger B, Miny P, Filges I, Dufke A, Andrieux J, Lee JA, Zink AM - Mol Cytogenet (2015)

Schematic representation of the microdeletions. Red bars: Microdeletions of patients 1 through 5 are presented. Grey bars: previously published microdeletions. Lower panel: detail with smallest region of overlap (SRO, dashed lines, red box) and RefSeq genes with black arrows showing direction of transcription (green: genes analyzed by expression studies)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4587785&req=5

Fig2: Schematic representation of the microdeletions. Red bars: Microdeletions of patients 1 through 5 are presented. Grey bars: previously published microdeletions. Lower panel: detail with smallest region of overlap (SRO, dashed lines, red box) and RefSeq genes with black arrows showing direction of transcription (green: genes analyzed by expression studies)
Mentions: In patients 1, 2, 4 and 5, de novo deletions in 9q33.3-q34.11 ranging from 1.23 to 4.13 Mb were detected using various array platforms (Table 1, Fig. 2). Interestingly, the smallest deletion was detected in patient 3, whose 432-kb deletion was inherited from her mother who is reported to have mild ID. The smallest region of overlap (SRO) is defined by the distal boundary of the deletion in patient 3 and the proximal deletion boundary in patient 5, and includes only two RefSeq genes, RALGPS1 and GARNL3. In patients 1, 2, 3 and 4, ANGPTL2 is also deleted. Importantly, the SRO does not include the STXBP1 gene in 9q34.11 (Fig. 2). No additional de novo CNVs or CNVs in known copy number-sensitive regions have been detected.Table 1

Bottom Line: The smallest region of overlap (SRO) of these deletions in 9q33.3 does not encompass STXBP1, but includes two genes that have not been previously associated with disease, RALGPS1 and GARNL3.Gene expression analyses in our patients demonstrated significantly reduced expression levels of GARNL3, RALGPS1 and STXBP1 only in patients with deletions of the corresponding genes.Thus, reduced expression of STXBP1 was ruled out as a cause for seizures in our patient whose deletion did not encompass STXBP1.

View Article: PubMed Central - PubMed

Affiliation: Institute of Human Genetics, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.

ABSTRACT

Background: Most microdeletions involving chromosome sub-bands 9q33.3-9q34.11 to this point have been detected by analyses focused on STXBP1, a gene known to cause early infantile epileptic encephalopathy 4 and other seizure phenotypes. Loss-of-function mutations of STXBP1 have also been identified in some patients with intellectual disability without epilepsy. Consequently, STXBP1 is widely assumed to be the gene causing both seizures and intellectual disability in patients with 9q33.3-q34.11 microdeletions.

Results: We report five patients with overlapping microdeletions of chromosome 9q33.3-q34.11, four of them previously unreported. Their common clinical features include intellectual disability, psychomotor developmental delay with delayed or absent speech, muscular hypotonia, and strabismus. Microcephaly and short stature are each present in four of the patients. Two of the patients had seizures. De novo deletions range from 1.23 to 4.13 Mb, whereas the smallest deletion of 432 kb in patient 3 was inherited from her mother who is reported to have mild intellectual disability. The smallest region of overlap (SRO) of these deletions in 9q33.3 does not encompass STXBP1, but includes two genes that have not been previously associated with disease, RALGPS1 and GARNL3. Sequencing of the two SRO genes RALGPS1 and GARNL3 in at least 156 unrelated patients with mild to severe idiopathic intellectual disability detected no causative mutations. Gene expression analyses in our patients demonstrated significantly reduced expression levels of GARNL3, RALGPS1 and STXBP1 only in patients with deletions of the corresponding genes. Thus, reduced expression of STXBP1 was ruled out as a cause for seizures in our patient whose deletion did not encompass STXBP1.

Conclusions: We suggest that microdeletions of this region on chromosome 9q cause a clinical spectrum including intellectual disability, developmental delay especially concerning speech, microcephaly, short stature, mild dysmorphisms, strabismus, and seizures of incomplete penetrance, and may constitute a new contiguous gene deletion syndrome which cannot completely be explained by deletion of STXBP1.

No MeSH data available.


Related in: MedlinePlus