Quantitative dissection of multilocus pathogenic variation in an Egyptian infant with severe neurodevelopmental disorder resulting from multiple molecular diagnoses.

TitleQuantitative dissection of multilocus pathogenic variation in an Egyptian infant with severe neurodevelopmental disorder resulting from multiple molecular diagnoses.
Publication TypeJournal Article
Year of Publication2022
AuthorsHerman, I, Jolly, A, Du, H, Dawood, M, Abdel-Salam, GMH, Marafi, D, Mitani, T, Calame, DG, Coban-Akdemir, Z, Fatih, JM, Hegazy, I, Jhangiani, SN, Gibbs, RA, Pehlivan, D, Posey, JE, Lupski, JR
JournalAm J Med Genet A
Volume188
Issue3
Pagination735-750
Date Published2022 03
ISSN1552-4833
KeywordsAnimals, Calpain, Egypt, Humans, Infant, Muscle Proteins, Muscular Dystrophies, Limb-Girdle, Mutation, Neurodevelopmental Disorders, Phenotype, Whole Exome Sequencing
Abstract

Genomic sequencing and clinical genomics have demonstrated that substantial subsets of atypical and/or severe disease presentations result from multilocus pathogenic variation (MPV) causing blended phenotypes. In an infant with a severe neurodevelopmental disorder, four distinct molecular diagnoses were found by exome sequencing (ES). The blended phenotype that includes brain malformation, dysmorphism, and hypotonia was dissected using the Human Phenotype Ontology (HPO). ES revealed variants in CAPN3 (c.259C > G:p.L87V), MUSK (c.1781C > T:p.A594V), NAV2 (c.1996G > A:p.G666R), and ZC4H2 (c.595A > C:p.N199H). CAPN3, MUSK, and ZC4H2 are established disease genes linked to limb-girdle muscular dystrophy (OMIM# 253600), congenital myasthenia (OMIM# 616325), and Wieacker-Wolff syndrome (WWS; OMIM# 314580), respectively. NAV2 is a retinoic-acid responsive novel disease gene candidate with biological roles in neurite outgrowth and cerebellar dysgenesis in mouse models. Using semantic similarity, we show that no gene identified by ES individually explains the proband phenotype, but rather the totality of the clinically observed disease is explained by the combination of disease-contributing effects of the identified genes. These data reveal that multilocus pathogenic variation can result in a blended phenotype with each gene affecting a different part of the nervous system and nervous system-muscle connection. We provide evidence from this n = 1 study that in patients with MPV and complex blended phenotypes resulting from multiple molecular diagnoses, quantitative HPO analysis can allow for dissection of phenotypic contribution of both established disease genes and novel disease gene candidates not yet proven to cause human disease.

DOI10.1002/ajmg.a.62565
Alternate JournalAm J Med Genet A
PubMed ID34816580
PubMed Central IDPMC8837671
Grant ListU54HG003273 / HG / NHGRI NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
K08 HG008986 / HG / NHGRI NIH HHS / United States
T32 NS043124 / NS / NINDS NIH HHS / United States
T32 GM007526 / GM / NIGMS NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
U01 HG011758 / HG / NHGRI NIH HHS / United States