A retrospective review of multiple findings in diagnostic exome sequencing: halF.A.re distinct and halF.A.re overlapping diagnoses

Abstract

PurposeWe evaluated clinical and genetic features enriched in patients with multiple Mendelian conditions to determine which patients are more likely to have multiple potentially relevant genetic findings (MPRF).MethodsResults of the first 7698 patients who underwent exome sequencing at Ambry Genetics were reviewed. Clinical and genetic features were examined and degree of phenotypic overlap between the genetic diagnoses was evaluated.ResultsAmong patients referred for exome sequencing, 2% had MPRF. MPRF were more common in patients from consanguineous families and patients with greater clinical complexity. The difference in average number of organ systems affected is small: 4.3 (multiple findings) vs. 3.9 (single finding) and may not be distinguished in clinic.ConclusionPatients with multiple genetic diagnoses had a slightly higher number of organ systems affected than patients with single genetic diagnoses, largely because the comorbid conditions affected overlapping organ systems. Exome testing may be beneficial for all cases with multiple organ systems affected. The identification of multiple relevant genetic findings in 2% of exome patients highlights the utility of a comprehensive molecular workup and updated interpretation of existing genomic data; a single definitive molecular diagnosis from analysis of a limited number of genes may not be the end of a diagnostic odyssey.

CAGI SickKids challenges: Assessment of phenotype and variant predictions derived from clinical and genomic data of children with undiagnosed diseases

“…The phenotype spectrum caused by pathogenic variants in a particular gene often expands over time with new information and identification of additional patients. In addition, ~5% of children evaluated for rare genetic disorders have more than one causal genomic variant (Smith et al, ; Stavropoulos et al, ). Furthermore, inheritance patterns for genes often change with improved knowledge and understanding.…”

Homozygous variants in AMPD2 and COL11A1 lead to a complex phenotype of pontocerebellar hypoplasia type 9 and Stickler syndrome type 2

“…Taken together, we believe that both AMPD2 and COL11A1 homozygous variants may both be disease‐causing in the patient, with the AMPD2 mutations leading to a complex neurodevelopmental phenotype falling within the spectrum described for PCH9, and the COL11A1 mutations leading to hearing loss and ophthalmologic complications. Multiple potentially relevant genetic findings occur in 0.9–4.0% of clinical whole exomes, and like in this situation, are more likely in consanguineous families and in patients with high medical complexity (Smith et al, ). These findings extend our understanding of the neuroimaging aspects of PCH9 to include white matter changes in a periventricular distribution akin to periventricular leukomalacia, as well as the possibility of neuronal migrational defects of an isolated periventricular heterotopic nodule.…”

A new allelic variant of periventricular nodular heterotopia type 7 in a patient with adrenogenital syndrome due to a 21-hydroxylase deficiency

“…Таким образом, у ребенка было подтверждено два независимых моногенных заболевания -адрено-генитальный синдром, обусловленный дефицитом 21-гидроксилазы с аутосомно-рецессивным типом наследования и узловая гетеротопия мозга 7 типа, наследующаяся аутосомно-доминантно. заболевания с доказанной функциональной значимостью находок разным набором методов обнаружено у 1,8 % пациентов [6]. В клинической практике наличие двух независимых наследственных заболеваний сильно осложняет постановку правильного диагноза и разработку терапевтической коррекции.…”