Skip to main content

01.12.2014 | Research | Ausgabe 1/2014 Open Access

Orphanet Journal of Rare Diseases 1/2014

X-exome sequencing in Finnish families with Intellectual Disability - four novel mutations and two novel syndromic phenotypes

Orphanet Journal of Rare Diseases > Ausgabe 1/2014
Anju K Philips, Auli Sirén, Kristiina Avela, Mirja Somer, Maarit Peippo, Minna Ahvenainen, Fatma Doagu, Maria Arvio, Helena Kääriäinen, Hilde Van Esch, Guy Froyen, Stefan A Haas, Hao Hu, Vera M Kalscheuer, Irma Järvelä
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1750-1172-9-49) contains supplementary material, which is available to authorized users.

Competing interests

We declare that we have no competing interest.

Authors’ contributions

IJ conceived the idea of the study. AS, KA, MS, HK, MP and MA were responsible for the clinical diagnosis of the patients. AKP designed the experiments, performed mutation analysis for the families, X-inactivation study and wrote the manuscript. HVE and GF analyzed family L107. FD and MAh were involved in the mutation analysis study of the family D174 and family D172. SAH, HU and VMK performed X-exome sequencing and bioinformatic analysis. All authors contributed to the final manuscript version.



X-linked intellectual disability (XLID) is a group of genetically heterogeneous disorders characterized by substantial impairment in cognitive abilities, social and behavioral adaptive skills. Next generation sequencing technologies have become a powerful approach for identifying molecular gene mutations relevant for diagnosis.

Methods & objectives

Enrichment of X-chromosome specific exons and massively parallel sequencing was performed for identifying the causative mutations in 14 Finnish families, each of them having several males affected with intellectual disability of unknown cause.


We found four novel mutations in known XLID genes. Two mutations; one previously reported missense mutation (c.1111C > T), and one novel frameshift mutation (c. 990_991insGCTGC) were identified in SLC16A2, a gene that has been linked to Allan-Herndon-Dudley syndrome (AHDS). One novel missense mutation (c.1888G > C) was found in GRIA3 and two novel splice donor site mutations (c.357 + 1G > C and c.985 + 1G > C) were identified in the DLG3 gene. One missense mutation (c.1321C > T) was identified in the candidate gene ZMYM3 in three affected males with a previously unrecognized syndrome characterized by unique facial features, aortic stenosis and hypospadia was detected. All of the identified mutations segregated in the corresponding families and were absent in > 100 Finnish controls and in the publicly available databases. In addition, a previously reported benign variant (c.877G > A) in SYP was identified in a large family with nine affected males in three generations, who have a syndromic phenotype.


All of the mutations found in this study are being reported for the first time in Finnish families with several affected male patients whose etiological diagnoses have remained unknown to us, in some families, for more than 30 years. This study illustrates the impact of X-exome sequencing to identify rare gene mutations and the challenges of interpreting the results. Further functional studies are required to confirm the cause of the syndromic phenotypes associated with ZMYM3 and SYP in this study.
Additional file 1: Table S1: List of all the variants identified using X-exome sequencing. (XLS 40 KB)
Additional file 2: Figure S1: X inactivation pattern of an affected carrier female III-6 in Family D301. (PNG 22 KB)
Authors’ original file for figure 1
Authors’ original file for figure 2
Authors’ original file for figure 3
Authors’ original file for figure 4
Authors’ original file for figure 5
Über diesen Artikel

Weitere Artikel der Ausgabe 1/2014

Orphanet Journal of Rare Diseases 1/2014 Zur Ausgabe