Diagnostic value of partial exome sequencing in developmental disorders

Abstract

Although intellectual disability is one of the major indications for genetic counselling, there are no homogenous diagnostic algorithms for molecular testing. While whole exome sequencing is increasingly applied, we questioned whether analyzing a partial exome, enriched for genes associated with Mendelian disorders, might be a valid alternative approach that yields similar detection rates but requires less sequencing capacities. Within this context 106 patients with different intellectual disability forms were analyzed for mutations in 4.813 genes after pre-exclusion of copy number variations by array-CGH. Subsequent variant interpretation was performed in accordance with the ACMG guidelines. By this, a molecular diagnosis was established in 34% of cases and candidate mutations were identified in additional 24% of patients. Detection rates of causative mutations were above 30%, regardless of further symptoms, except for patients with seizures (23%). We did not detect an advantage from partial exome sequencing for patients with severe intellectual disability (36%) as compared to those with mild intellectual disability (44%). Specific clinical diagnoses pre-existed for 20 patients. Of these, 5 could be confirmed and an additional 6 cases could be solved, but showed mutations in other genes than initially suspected. In conclusion partial exome sequencing solved >30% of intellectual disability cases, which is similar to published rates obtained by whole exome sequencing. The approach therefore proved to be a valid alternative to whole exome sequencing for molecular diagnostics in this cohort. The method proved equally suitable for both syndromic and non-syndromic intellectual disability forms of all severity grades.

Fig 1. Photographs of patient #15 (MECP2 mutation).

The patient at 3 years and 6 months. The patient was diagnosed with a de novo mutation p.(Arg133Cys) in MECP2. Note arched eyebrows with slight synophrys, short anteverted nose, thin upper lip and smooth long philtrum.

Fig 2. Photographs of patients #29 (MED13L mutation).

The patient at 4 years and 2 months of age. He was diagnosed with MED13L syndrome. Note long eyelashes, broad nasal tip and open mouth appearance as well as preauricular tags.

Fig 3. Sequence coverage and occurrence of ADAMTSL2 variants.

The data is shown in the UCSC genome browser “multi region view” (http://genome.ucsc.edu), which displays exons in full length (dark blue boxes), flanked by 50 bp of intronic sequence (dark blue vertical line). The scale on top refers to the condensed sequence shown here. The full ADAMTSL2 gene comprises 40.6 kb of genomic DNA (chr9:136399975–136440641, hg19). Green: read coverage, target position and variants identified in this cohort; black: corresponding data in gnomAD.