Rapid Mendelian Genes Sequencing Panel, Trio

Rapid Mendelian Genes Sequencing Panel, Trio 2012849
Method: Massively Parallel Sequencing

Order for rapid diagnosis of a critically ill individual suspected to be affected with a Mendelian genetic condition

Mendelian diseases are inherited conditions linked to individual genes. This test entails rapid sequencing of ~4,900 genes of known function from a critically ill individual and both parents to quickly diagnose a Mendelian disease to improve medical management. 

Test Overview

  • Although humans have ~19,000 genes, the function of only ~4,900 genes is known.
    • This test only sequences genes with known function
  • See Rapid Mendelian Sequencing Gene List for genes included in this panel.
  • Parental specimens are required to identify de novo variants and to determine phase and clinical significance of variants detected in proband.

Required for Testing

Test Interpretation

Clinical Sensitivity

50% for infants (Willig, 2015; Daoud, 2016)

Reporting and Interpretation

  • Accurate representation of biological relationships between family members is imperative for correct test interpretation.
  • Only variants predicted to be related to the patient’s medical issues are reported.
  • Interpretation is based on information available at the time of testing and may change in the future.
  • Results are typically reported in 14-28 days.

Secondary Findings

  • American College of Medical Genetics and Genomics (ACMG) recommends that disease-causing variants in specific genes (see ACMG list in table below) be reported whether or not they are related to the patient’s medical issues (Kalia, 2016).
    • This information may enable disease monitoring or early treatment.
    • Single pathogenic variants in autosomal recessive genes from this list are not reported.
  • Additional medically actionable secondary findings may be reported at ARUP’s discretion.
  • Pathogenic variants in genes recommended by ACMG, or other medically actionable secondary findings in non-ACMG genes, are reported if elected on the consent form.
  • Parental inheritance is not reported for secondary variants detected in the proband.
  • Parents are not issued reports of secondary findings.
  • Familial Mutation, Targeted Sequencing (2001961) can be ordered on the parents to test for a medically actionable secondary finding reported in the proband.

Limitations

  • A negative result does not exclude the possibility of a genetic condition.
  • Diagnostic errors can occur due to rare sequence variations.
  • Interpretation of this test result may be impacted if the individual or his/her parents have had an allogeneic stem cell transplantation.
  • The following will not be evaluated:
    • Genes with unknown function
    • Variants outside coding regions and intron-exon boundaries of the targeted genes
    • Regulatory region variants and deep intronic variants
    • Large deletions/duplications
    • Noncoding transcripts
  • The following may not be detected:
    • Deletions/duplications/insertions of any size by massively parallel sequencing
    • Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
    • Pathogenic ACMG variants that cannot be detected by massively parallel sequencing
    • Low-level mosaic variants

Analytic Sensitivity

For massively parallel sequencing:

Variant Class

Analytical Sensitivity (PPA) Estimatea (%)

Analytical Sensitivity (PPA) 95% Credibility Regiona (%)

SNVs

99.2

96.9-99.4

Deletions 1-10 bp

93.8

84.3-98.2

Deletions 11-44 bp

100

87.8-100

Insertions 1-10 bp

94.8

86.8-98.5

Insertions 11-23 bp

100

62.1-100

aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived.

bp, base pairs; PPA, positive percent agreement; SNVs, single nucleotide variants

ACMG (Kalia, 2016) Recommends Reporting Secondary Findings for These Genes
Conditions Associated Genes

Tumors/cancer syndromes

Familial adenomatous polyposis

APC

Familial medullary thyroid cancer

Multiple endocrine neoplasia type 2

RET

Hereditary breast and ovarian cancer

BRCA1, BRCA2

Hereditary paraganglioma/pheochromocytoma

SDHD, SDHAF2, SDHC, SDHB

Juvenile polyposis

BMPR1A, SMAD4

Li-Fraumeni syndrome

TP53

Lynch syndrome

MLH1, MSH2, MSH6, PMS2

Multiple endocrine neoplasia type 1

MEN1

MUTYH-associated polyposis

MUTYH

Neurofibromatosis type 2

NF2

Peutz-Jeghers syndrome

STK11

PTEN hamartoma tumor syndrome

PTEN

Retinoblastoma

RB1

Tuberous sclerosis complex

TSC1, TSC2

Von Hippel-Lindau syndrome

VHL

WT1-related Wilms tumor

WT1

Cardiovascular conditions/syndromes

Arrhythmogenic right-ventricular cardiomyopathy

PKP2, DSP, DSC2, TMEM43, DSG2

Brugada syndrome

Romano-Ward long QT syndrome types 1, 2, and 3

KCNQ1, KCNH2, SCN5A

Catecholaminergic polymorphic ventricular tachycardia

RYR2

Ehlers-Danlos syndrome, vascular type

COL3A1

Familial hypercholesterolemia

LDLR, APOB, PCSK9

Familial thoracic aortic aneurysms and dissections

SMAD3, ACTA2, MYLK, MYH11

Hypertrophic cardiomyopathy, dilated cardiomyopathy

MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL3, ACTC1, PRKAG2, GLA, MYL2, LMNA

Loeys-Dietz

TGFBR1, TGFBR2

Marfan syndrome

FBN1

Other conditions

Malignant hyperthermia susceptibility

RYR1, CACNA1S

Ornithine transcarbamylase deficiency

OTC

Wilson disease

ATP7B

References 

Daoud H, Luco SM, Li R, Bareke E, Beaulieu C, Jarinova O, Carson N, Nikkel SM, Graham GE, Richer J, Armour C, Bulman DE, Chakraborty P, Geraghty M, Lines MA, Lacaze-Masmonteil T, Majewski J, Boycott KM, Dyment DA. Next-generation sequencing for diagnosis of rare diseases in the neonatal intensive care unit. CMAJ. 2016; 188(11): E254-60. PubMed

Kalia SS, Adelman K, Bale SJ, Chung WK, Eng C, Evans JP, Herman GE, Hufnagel SB, Klein TE, Korf BR, McKelvey KD, Ormond KE, Richards S, Vlangos CN, Watson M, Martin CL, Miller DT. Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics Genet Med. 2016; PubMed

Willig LK, Petrikin JE, Smith LD, Saunders CJ, Thiffault I, Miller NA, Soden SE, Cakici JA, Herd SM, Twist G, Noll A, Creed M, Alba PM, Carpenter SL, Clements MA, Fischer RT, Hays A, Kilbride H, McDonough RJ, Rosterman JL, Tsai SL, Zellmer L, Farrow EG, Kingsmore SF. Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of diagnostic and clinical findings. Lancet Respir Med. 2015; 3(5): 377-87. PubMed

Last Update: February 2019