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Table 2 Lessons learned that may increase the molecular diagnostic yield from unsolved clinical exomes

From: Lessons learned from additional research analyses of unsolved clinical exome cases

Lesson Learned Examples
A) Collaboration between research and clinical laboratories Sharing data, open communication of findings, access to additional patients with damaging variants
B) Facilitating research collaborations including local and international efforts GeneMatcher for the identification of unrelated affected individuals with the same novel disease
C) Ancillary approaches to enhance molecular diagnostic rate:  
1) Detection of AOH and CNVs from WES 2) Annotation of single exon genes 3) Analyze intronic variants (including those in the unfiltered vcf files) 4) Optimization of the bioinformatic filters 5) Look for in trans inheritance of SNVs and CNVs 6) Increase fidelity of calling dinucleotide substitutions 1) ABCA4, SLC1A4, TANGO2, FBXL4 2) PURA, GSPT2 3) TRAPPC11 4) ABCA4, NRXN3 5) TANGO2 a , MIPEP 6) SYN3
D) Ancillary approaches for non-conclusive WES:  
1) Consider dual molecular diagnoses 2) Analyze additional family members 3) Look for parental mosaicism 4) Identify homozygous stop-gain SNVs from bulk data to identify additional affected individuals 1) PMPCA and KCND3; POLR1C and SCN1B a 2) SLC13A5, NAA10 3) PIK3CD 4) GNB5 a
E) Consideration of different inheritance patterns and variant types at a single locus  
1) AR, AD 2) AD, CNV del 3) AR, CNV del 4) XLR, CNV dup 5) AD, Tandem repeats 6) AR, AR 1) ATAD3A, EBF3, EMC1, GSPT2, NALCN, GUCY2C 2) EBF3, PURA, ZBTB20 3) NRXN3 4) GSPT2 5) CACNA1A a 6) POLR1C
  1. aThe molecular diagnosis in these genes had direct implications for clinical management
  2. AD autosomal dominant, AOH absence of heterozygozity, AR autosomal recessive, del deletion, dup duplication, CNV copy number variation, SNV single nucleotide variants, WES whole exome sequencing, WGS whole genome sequencing, XLR X-linked recessive