Making headway with genetic diagnostics of intellectual disabilities

Willemsen, Marjolein H.; Kleefstra, Tjitske

doi:10.1111/cge.12244

Cited by 43 publications

(35 citation statements)

References 90 publications

(213 reference statements)

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“…The recent development of sequencing technologies has provided an effective tool to analyze the chromosomal distribution of mutations underlying ID [5-10]. Sequencing of the coding regions of the X-chromosome in families with multiple affected males has resulted in the identification of about 100 XLID genes to date [11].…”

Section: Introductionmentioning

confidence: 99%

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

Philips

Siren

Avela³

et al. 2014

Orphanet J Rare Dis

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BackgroundX-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 & objectivesEnrichment 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.ResultsWe 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.ConclusionsAll 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.

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Section: Introductionmentioning

confidence: 99%

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

Philips

Siren

Avela³

et al. 2014

Orphanet J Rare Dis

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“…The implementation of genome-wide technologies such as microarray analysis and whole exome sequencing (WES) has dramatically increased the diagnostic yield (1). Finding the correct genetic diagnosis poses a major challenge even for experienced clinical geneticists.…”

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confidence: 99%

Expanding the phenotype of a recurrent de novo variant in PACS1 causing intellectual disability

et al. 2014

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“…2 Despite the considerable progress in disease gene identification, especially after the introduction of nextgeneration sequencing, at least 50% of the estimated genetic causes of ID remain unknown. 3 All Mendelian inheritance patterns have been reported with ID, and approximately half of them follow an autosomal recessive inheritance pattern (autosomal recessive intellectual disability). 3 The study of consanguineous families has facilitated the discovery of pathogenic genetic variants in many autosomal recessive disorders.…”

Section: Introductionmentioning

confidence: 99%

“…3 All Mendelian inheritance patterns have been reported with ID, and approximately half of them follow an autosomal recessive inheritance pattern (autosomal recessive intellectual disability). 3 The study of consanguineous families has facilitated the discovery of pathogenic genetic variants in many autosomal recessive disorders. [4][5][6] The frequency of autosomal recessive disorders is higher in populations where consanguineous marriages are frequent.…”

Section: Introductionmentioning

confidence: 99%

Biallelic variants in LINGO1 are associated with autosomal recessive intellectual disability, microcephaly, speech and motor delay

Ansar

Riazuddin

Sarwar

et al. 2018

Genetics in Medicine

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Purpose: To elucidate the novel molecular cause in two unrelated consanguineous families with autosomal recessive intellectual disability.Methods: A combination of homozygosity mapping and exome sequencing was used to locate the plausible genetic defect in family F162, while only exome sequencing was followed in the family PKMR65. The protein 3D structure was visualized with the University of California-San Francisco Chimera software.Results: All five patients from both families presented with severe intellectual disability, aggressive behavior, and speech and motor delay. Four of the five patients had microcephaly. We identified homozygous missense variants in LINGO1, p.(Arg290His) in family F162 and p.(Tyr288Cys) in family PKMR65. Both variants were predicted to be pathogenic, and segregated with the phenotype in the respective families. Molecular modeling of LINGO1 suggests that both variants interfere with the glycosylation of the protein.Conclusion: LINGO1 is a transmembrane receptor, predominantly found in the central nervous system. Published loss-offunction studies in mouse and zebrafish have established a crucial role of LINGO1 in normal neuronal development and central nervous system myelination by negatively regulating oligodendrocyte differentiation and neuronal survival. Taken together, our results indicate that biallelic LINGO1 missense variants cause autosomal recessive intellectual disability in humans.

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Making headway with genetic diagnostics of intellectual disabilities

Cited by 43 publications

References 90 publications

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

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

Expanding the phenotype of a recurrent de novo variant in PACS1 causing intellectual disability

Biallelic variants in LINGO1 are associated with autosomal recessive intellectual disability, microcephaly, speech and motor delay

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