Recent research shows clinical applications of exome sequences in diagnosing in neurodevelopmental diseases
When all four children in a single family began to develop hearing, speech and intellectual defects as infants, doctors performed routine medical and genetic tests to diagnose their condition. The tests revealed little, and the children were diagnosed with a recessive form of intellectual disability, with no apparent heritable cause. Intellectual disability, like most neurodevelopmental disorders, can be particularly tricky to identify because of the lack of precise diagnostic tests and difficulty of obtaining tissue biopsies. Researchers probing the genetics underlying such conditions recently sequenced the exomes of this family and over a hundred others with affected children, implicating several novel genes in the development of these disorders. Their research, published in Science Translational Medicine last month, also hints at ways to adopt exome sequencing in clinical practice.
To identify the best candidates for exome analysis, the researchers chose families with at least two affected children, as well as a history of marrying amongst relatives. In such cases, the probability of a causative genetic variant being inherited in a recessive Mendelian pattern is significantly higher, narrowing the list of potential genetic culprits and making them easier to identify.
Extracting DNA from blood samples, the researchers began by testing for SNPs already linked to these diseases. Of the 188 affected individuals, forty turned out to have such mutations and were excluded from further genetic analysis. As the efficiency of exome sequencing and analysis improves, it may prove simpler to perform than such individual tests at multiple loci.
In thirty other families, the scientists found only one significant variant that followed the inheritance patterns expected for a potentially disease-causing mutation. In all cases, this variant was a novel SNP so far unlinked to neurodevelopmental disorders. Sequencing samples from the remaining 118 patients, the researchers identified 2-3 candidate loci per individual that were likely to be associated with their conditions. Ten of these families had mutations in known genes that were missed by the earlier genetic tests. In all these cases, the mutation identified explained all the clinical symptoms of the children, and helped to correct diagnosis or prescribe better treatment plans.
The family with four intellectually disabled children turned out to be one of these ten. Though the children had tested negative for mutations in VPSB13B, a gene linked to poor intellectual development, their exome sequences revealed a mutation in the MAN2B1 gene that produced a truncated, ineffective protein. Disruptive MAN2B1 mutations cause α-mannosidosis, a lysosomal storage disorder resulting from an inability to digest glycoproteins inside cells. Re-evaluating the children’s clinical profiles, the team found that all their clinical symptoms could be explained by this one mutation. Unlike recessive intellectual disability, α-mannosidosis can be treated with hematopoeitic stem cell transplants that produce the missing enzyme, which have proved effective in some patients with lysosomal storage disorders.
Variants identified in the other nine families also helped to correct or clarify diagnoses for the affected children. In all these cases, the mutations identified in exome analysis helped the researchers better understand the course of the disease or improve the therapeutic regimens prescribed to the patients. The several novel variants identified in the remaining families are still being studied for their relevance to neurodevelopmental diseases. They may also prove to be relevant in broader populations, eventually building towards a database of genetic variants associated with neurodevelopmental disorders.
Perhaps more importantly however, the results of this study hint at ways to address the larger issue of the relevance of whole exome sequencing in the clinic. The diagnostic value of exome sequencing is still emerging from a cloud of concerns about data quality, cost of interpretation, ownership of an individual’s data and when to best apply such genome-wide analysis. The filtering used in this study to identify the patients most likely benefit from exome sequencing could address some of these concerns.
Tracy J. Dixon-Salazar1,, Jennifer L. Silhavy1,, Nitin Udpa2,, Jana Schroth1,, Stephanie Bielas1,, Ashleigh E. Schaffer1,, Jesus Olvera1,, Vineet Bafna2,, Maha S. Zaki3,, Ghada H. Abdel-Salam3,, Lobna A. Mansour4,, Laila Selim4,, Sawsan Abdel-Hadi4,, Naima Marzouki5,, Tawfeg Ben-Omran6,, Nouriya A. Al-Saana7,, F. Müjgan Sonmez8,, Figen Celep9,, Matloob Azam10,, Kiley J. Hill1,, Adrienne Collazo1,, Ali G. Fenstermaker1,, Gaia Novarino1,, Naiara Akizu1,, Kiran V. Garimella11,, Carrie Sougnez11,, Carsten Russ11,, Stacey B. Gabriel11,* and, & Joseph G. Gleeson1,*,† (2012). Exome Sequencing Can Improve Diagnosis and Alter Patient Management Science Translational Medicine DOI: 10.1126/scitranslmed.3003544SHARE