We perform exome/genome sequencing and data analysis to identify disease genes on rare undiagnosed diseases.


A significant number of rare Mendelian diseases, especially those involving neuronal phenotypes, remain undiagnosed or misdiagnosed. Accurate genetic diagnosis may potentially benefit disease management or treatment. We have developed multiple collaborations with researchers on rare undiagnosed diseases to apply exome/genome sequencing for disease gene finding.

Genome/exome sequencing can quickly identify disease genes for known diseases, or identify novel candidate genes for novel syndromes. Several examples are given below:

1. IHA (known disease)

In collaboration with Dr. Gholson Lyon, we sequenced a pedigree segregating both a complex disease (ADHD) and a Mendelian disease (hemolytic anemia). While we did identify some rare variants that might predispose to ADHD, we have not yet proven the causality for any of them. However, over the course of the study, one subject was discovered to have idiopathic hemolytic anemia (IHA), which was suspected to be genetic in origin. Analysis of this subject’s exome readily identified two rare non-synonymous mutations in PKLR gene as the most likely cause of the IHA. We further confirmed the deficiency by functional biochemical testing, consistent with a diagnosis of red blood cell pyruvate kinase deficiency.

2. MPS3B (known disease)

We encountered a case in China where two siblings both began to develop idiopathic progressive cognitive decline starting from age six, and were suspected to have an undiagnosed neurological disease. Exome sequencing identified NAGLU as the most likely candidate gene with compound heterozygous mutations. Sanger sequencing confirmed the recessive patterns of inheritance, leading to a genetic diagnosis of Sanfilippo syndrome (mucopolysaccharidosis IIIB). Biochemical tests confirmed the complete loss of activity of alpha-N-acetylglucosaminidase (encoded by NAGLU) in blood, as well as significantly elevated dermatan sulfate and heparan sulfate in urine. Structure modeling revealed the mechanism on how the two variants affect protein structural stability.

3. Ogden syndrome (novel syndrome)

One of the early examples to identify genes for "novel syndrome" was Ogden syndrome, a previously unreported infantile lethal disorder, involving a mutation in NAA10. Together with Dr. Gholson, we identified the disease gene by chromosome exon X capture and next-generation sequencing.

4. RBCK1 deficiency syndrome (novel syndrome)

A more recent example is a novel genetic disease which we refer to as "Bookman syndrome", a pediatric onset disease with neuromuscular and cardiac involvement and with clinical features similar to Glycogen Storage Disease Type IV. Although exome sequencing failed to identify the causes for the disease due to technical reasons, we applied genome and transcriptome sequencing and identified a disease-contributory mutation in RBCK1, which was further replicated by another group. This disease is now referred to as RBCK1 deficiency syndrome nowadays.

5. TAF1 deficiency syndrome (novel syndrome)

In collaboration with Dr. Lyon, we analyzed an extended family with three generations, and sequenced them by Illumina WGS and Complete Genomics WGS. Two affecteds in the third generation are both affected with severe intellectual disability, autistic behaviors, ADHD, and very distinctive facial features. Family-based analysis pinpointed TAF1 as the most likely candidate gene. Interestingly, the X-linked non-synonymous mutation in TAF1 was detected as a de novo mutation arising in the mother of the two affecteds.

6. Age-related macular degeneration (known disease)

In collaboration with Dr. Huang, we are analyzing over 100 families with various types of eye diseases, especially those with dry/wet type of age-related macular degeneration, to identify new genes responsible for these rare genetic syndromes. The wet/neovascular type affects approximately 10-15% of individuals with age-related macular degeneration, but accounts for approximately 90% of all cases of severe vision loss from the disease.

7. Odentogenic keratocysts (known disease)

In collaboration with Dr. Chen, we are identifying additional genes that may underlie susceptibility to Odentogenic keratocysts. Odontogenic keratocyst (OKC) is a locally aggressive developmental cystic neoplasm with a propensity for recurrence. Approximately 80% sporadic OKCs harbor PTCH1 mutation. Nevertheless, the tumorigenesis of about 20% OKCs with no PTCH1 mutation remain to be further studied.

These examples clearly illustrated the power of genome seuqencing in uncovering genetic basis for rare undiagnosed diseases.