Genetic underpinnings of Wiedemann-Steiner syndrome identified

By MedWire Reporters

Researchers have identified a genetic underpinning of Wiedemann-Steiner syndrome (WSS).

Utilizing a whole-exome sequencing approach, the group identified de novo mutations in the mixed lineage leukemia (MLL) gene in five of six individuals with the syndrome.

MLL is a histone methyltransferase that regulates gene transcription. It regulates chromatin-mediated transcription through the catalysis of methylation of histone H3K4.

"Each of the five mutations is predicted to result in premature termination of the protein product," report Michael Simpson (King's College London School of Medicine, UK) and colleagues in the American Journal of Human Genetics.

Nonandrogen-related excessive growth of terminal hair around the elbows, known as hypertrichosis cubiti, has been reported alone and in association with a spectrum of phenotypic features.

Six individuals with hypertrichosis cubiti were identified and they all had short stature, intellectual disability, and a distinctive facial appearance, such as long eyelashes, thick or arched eyebrows, and downslanting and vertically narrow palpebral fissures, consistent with WSS.

In the present study, the researchers attempted to identify a genetic basis of congenital hypertrichosis cubiti. Using a whole-exome strategy, they sought to identify disease-causing alleles in the six individuals.

Examining the exome variant profiles of affected cases under the assumption that the causative alleles were dominant and had arisen de novo, they identified MLL as a candidate gene with previously unidentified heterozygous variants in five of the six individuals.

The researchers noted that the mutations in the MLL gene led to a premature termination of the MLL protein, leading to a lack of histone-methyltransferase activity.

In addition, they report that transcripts arising from the mutant alleles undergo nonsense-mediated decay.

According to Simpson and colleagues, these findings define the genetic basis of WSS, and "provide additional evidence for the role of haplo-insufficiency of histone modification enzymes in multiple-congenital-anomaly syndromes."

The phenotypic features of WSS are likely the result of secondary downstream effects on transcription via the genomic distribution and the timing of the histone-methylation events, they add.

MLL is expressed in most cell types, but has been widely studied in hematologic malignancies. The MLL locus is known to be the site of somatic chromosome translocations in acute myeloid, acute lymphoblastoid, or mixed-lineage leukemia.

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