Clinical Exome Sequencing: Hope for Rare Genetic Diseases?

Biomedical researchers have often been insulated from the patients they’re studying. At such a distance, it’s sometimes hard to appreciate the day-to-day struggle of people with genetic diseases.  That’s why I like this dual perspective: A study in the Journal of Medical Genetics describes the exome sequencing of 12 patients rare genetic conditions; accompanying it is Hunting Down My Son’s Killer, a blog post by the father of one of the patients chronicling his family’s struggle in understanding the boy’s disease.

You should read both. On one hand, we have the study, in which David Goldstein and colleagues at Duke University describe the exome sequencing of 12 families with unknown but likely genetic diseases. These families met two or more of the following criteria:

  1. Unexplained intellectual disability and/or developmental delay;
  2. One major congenital anomaly;
  3. 2–3 minor congenital anomalies
  4. Facial dysmorphisms

Additionally, the researchers required that the proband and both unaffected parents were available for exome sequencing, that previous genetic testing (Affy 6.0 SNP array) had been normal, and that there were no teratogenic or accidental events in the proband’s life that might be causal.

Their analysis also made use of 830 presumably-undiseased control samples that were enrolled at Duke for human genome variation studies.

Variant Identification and Filtering

With exome sequence data in hand, Dr. Goldstein and colleagues began the search for potential disease-causing variants. They were looking in particular for:

  1. Putative recessive or X-linked variants that were homozygous in the proband and but never homozygous in the parents or any control.
  2. Putative de novo variants heterozygous in the proband but absent from parents.
  3. Compound protein-altering (missense/nonsense/frameshift) heterozygotes in a single gene that did not occur together in the parents or controls.

The authors generated, and confirmed in a CLIA setting, the likely genetic diagnosis for 6 of 12 patients studied.

One Family’s Struggle

On the other side, the patients’ side, is a riveting tale of parents whose son began showing signs of developmental delay at 3 months. A suite of other symptoms followed, accompanied by various hospitalizations, mis-diagnoses, and failed treatments. Several times, the father writes, someone would ask him and his wife “Are you two sure you’re not related?” He’s from an Ohio farm family and she’s from Puerto Rico. So, no. (And, “Duh!”).

Alternatively, some doctors took the wife aside and asked, “Is it possible he’s not the actual father?” Wow, great bedside manner.

At last, the exome sequencing study revealed a likely genetic cause for the boy’s disorder, and suggested a potential treatment. A good thing on both accounts, as the mother was pregnant again. They had a daughter who, fortunately, did not carry the mutation.

This is just one family’s chronicle – there are eleven other families with similar struggles whose story we haven’t heard, and six of them, sadly, have not yet found the answer in exome sequencing.

Need AC, Shashi V, Hitomi Y, Schoch K, Shianna KV, McDonald MT, Meisler MH, & Goldstein DB (2012). Clinical application of exome sequencing in undiagnosed genetic conditions. Journal of medical genetics PMID: 22581936

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