Open AccessANKLE2 ‐related microcephaly: A variable microcephaly syndrome resembling Zika infection
Author(s) -
Thomas Ajay X.,
Link Nichole,
Robak Laurie A.,
DemmlerHarrison Gail,
Pao Emily C.,
Squire Audrey E.,
Michels Savannah,
Cohen Julie S.,
Comi Anne,
Prontera Paolo,
Verrotti di Pianella Alberto,
Di Cara Giuseppe,
Garavelli Livia,
Caraffi Stefano Giuseppe,
Fusco Carlo,
Zuntini Roberta,
Parks Kendall C.,
Sherr Elliott H.,
Hashem Mais O.,
Maddirevula Sateesh,
Alkuraya Fowzan S.,
Contractar Isphana A. F.,
Neil Jennifer E.,
Walsh Christopher A.,
Bellen Hugo J.,
Chao HsiaoTuan,
Clark Robin D.,
Mirzaa Ghayda M.
Publication year - 2022
Publication title -
annals of clinical and translational neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.824
H-Index - 42
ISSN - 2328-9503
DOI - 10.1002/acn3.51629
Subject(s) - microcephaly , zika virus , proband , medicine , phenotype , hypoplasia , genetics , agenesis , biology , anatomy , gene , mutation , virus
Objective This study delineates the clinical and molecular spectrum of ANKLE2 ‐related microcephaly (MIC), as well as highlights shared pathological mechanisms between ANKLE2 and the Zika virus. Methods We identified 12 individuals with MIC and variants in ANKLE2 with a broad range of features. Probands underwent thorough phenotypic evaluations, developmental assessments, and anthropometric measurements. Brain imaging studies were systematically reviewed for developmental abnormalities. We functionally interrogated a subset of identified ANKLE2 variants in Drosophila melanogaster . Results All individuals had MIC ( z ‐score ≤ −3), including nine with congenital MIC. We identified a broad range of brain abnormalities including simplified cortical gyral pattern, full or partial callosal agenesis, increased extra‐axial spaces, hypomyelination, cerebellar vermis hypoplasia, and enlarged cisterna magna. All probands had developmental delays in at least one domain, with speech and language delays being the most common. Six probands had skin findings characteristic of ANKLE2 including hyper‐ and hypopigmented macules. Only one individual had scalp rugae. Functional characterization in Drosophila recapitulated the human MIC phenotype. Of the four variants tested, p.Val229Gly, p.Arg236*, and p.Arg536Cys acted as partial‐loss‐of‐function variants, whereas the c.1421‐1G>C splicing variant demonstrated a strong loss‐of‐function effect. Interpretation Deleterious variants in the ANKLE2 gene cause a unique MIC syndrome characterized by congenital or postnatal MIC, a broad range of structural brain abnormalities, and skin pigmentary changes. Thorough functional characterization has identified shared pathogenic mechanisms between ANKLE2‐ related MIC and congenital Zika virus infection. This study further highlights the importance of a thorough diagnostic evaluation including molecular diagnostic testing in individuals with MIC.