Clinical Characterization and Underlying Genetic Findings in Brazilian Patients with Syndromic Microcephaly Associated with Neurodevelopmental Disorders

Microcephaly is characterized by an occipitofrontal circumference at least two standard deviations below the mean for age and sex. Neurodevelopmental disorders (NDD) are commonly associated with microcephaly, due to perturbations in brain development and functioning. Given the extensive genetic heterogeneity of microcephaly, managing patients is hindered by the broad spectrum of diagnostic possibilities that exist before conducting molecular testing. We investigated the genetic basis of syndromic microcephaly accompanied by NDD in a Brazilian cohort of 45 individuals and characterized associated clinical features, as well as evaluated the effectiveness of whole-exome sequencing (WES) as a diagnostic tool for this condition. Patients previously negative for pathogenic copy number variants underwent WES, which was performed using a trio approach for isolated index cases (n = 31), only the index in isolated cases with parental consanguinity (n = 8) or affected siblings in familial cases (n = 3). Pathogenic/likely pathogenic variants were identified in 19 families (18 genes) with a diagnostic yield of approximately 45%. Nearly 86% of the individuals had global developmental delay/intellectual disability and 51% presented with behavioral disturbances. Additional frequent clinical features included facial dysmorphisms (80%), brain malformations (67%), musculoskeletal (71%) or cardiovascular (47%) defects, and short stature (54%). Our findings unraveled the underlying genetic basis of microcephaly in half of the patients, demonstrating a high diagnostic yield of WES for microcephaly and reinforcing its genetic heterogeneity. We expanded the phenotypic spectrum associated with the condition and identified a potentially novel gene (CCDC17) for congenital microcephaly.

References

Wilsch-Brauninger M, Huttner W . Primary Cilia and Centrosomes in Neocortex Development. Front Neurosci. 2021; 15:755867. PMC: 8566538. DOI: 10.3389/fnins.2021.755867. View

Xing L, Wilsch-Brauninger M, Huttner W . How neural stem cells contribute to neocortex development. Biochem Soc Trans. 2021; 49(5):1997-2006. PMC: 8589419. DOI: 10.1042/BST20200923. View

von der Hagen M, Pivarcsi M, Liebe J, von Bernuth H, DiDonato N, Hennermann J . Diagnostic approach to microcephaly in childhood: a two-center study and review of the literature. Dev Med Child Neurol. 2014; 56(8):732-41. DOI: 10.1111/dmcn.12425. View

Boonsawat P, Joset P, Steindl K, Oneda B, Gogoll L, Azzarello-Burri S . Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly. Genet Med. 2019; 21(9):2043-2058. PMC: 6752480. DOI: 10.1038/s41436-019-0464-7. View

Gilmore E, Walsh C . Genetic causes of microcephaly and lessons for neuronal development. Wiley Interdiscip Rev Dev Biol. 2013; 2(4):461-78. PMC: 3767923. DOI: 10.1002/wdev.89. View

Ashwal S, Michelson D, Plawner L, Dobyns W . Practice parameter: Evaluation of the child with microcephaly (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. 2009; 73(11):887-97. PMC: 2744281. DOI: 10.1212/WNL.0b013e3181b783f7. View

Sena Amaral M, Goulart E, Caires-Junior L, Morales-Vicente D, Soares-Schanoski A, Gomes R . Differential gene expression elicited by ZIKV infection in trophoblasts from congenital Zika syndrome discordant twins. PLoS Negl Trop Dis. 2020; 14(8):e0008424. PMC: 7425990. DOI: 10.1371/journal.pntd.0008424. View

Masih S, Moirangthem A, Shambhavi A, Rai A, Mandal K, Saxena D . Deciphering the molecular landscape of microcephaly in 87 Indian families by exome sequencing. Eur J Med Genet. 2022; 65(6):104520. DOI: 10.1016/j.ejmg.2022.104520. View

Gilissen C, Hehir-Kwa J, Tjwan Thung D, van de Vorst M, van Bon B, Willemsen M . Genome sequencing identifies major causes of severe intellectual disability. Nature. 2014; 511(7509):344-7. DOI: 10.1038/nature13394. View

10.

Parenti I, Rabaneda L, Schoen H, Novarino G . Neurodevelopmental Disorders: From Genetics to Functional Pathways. Trends Neurosci. 2020; 43(8):608-621. DOI: 10.1016/j.tins.2020.05.004. View

11.

Vissers L, van Nimwegen K, Schieving J, Kamsteeg E, Kleefstra T, Yntema H . A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology. Genet Med. 2017; 19(9):1055-1063. PMC: 5589982. DOI: 10.1038/gim.2017.1. View

12.

Tawamie H, Martianov I, Wohlfahrt N, Buchert R, Mengus G, Uebe S . Hypomorphic Pathogenic Variants in TAF13 Are Associated with Autosomal-Recessive Intellectual Disability and Microcephaly. Am J Hum Genet. 2017; 100(3):555-561. PMC: 5339287. DOI: 10.1016/j.ajhg.2017.01.032. View

13.

Farooq M, Lindbaek L, Krogh N, Doganli C, Keller C, Monnich M . RRP7A links primary microcephaly to dysfunction of ribosome biogenesis, resorption of primary cilia, and neurogenesis. Nat Commun. 2020; 11(1):5816. PMC: 7670429. DOI: 10.1038/s41467-020-19658-0. View

14.

Robinson P, Kohler S, Bauer S, Seelow D, Horn D, Mundlos S . The Human Phenotype Ontology: a tool for annotating and analyzing human hereditary disease. Am J Hum Genet. 2008; 83(5):610-5. PMC: 2668030. DOI: 10.1016/j.ajhg.2008.09.017. View

15.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J . Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015; 17(5):405-24. PMC: 4544753. DOI: 10.1038/gim.2015.30. View

16.

Miller D, Lee K, Chung W, Gordon A, Herman G, Klein T . ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021; 23(8):1381-1390. DOI: 10.1038/s41436-021-01172-3. View

17.

Fromer M, Moran J, Chambert K, Banks E, Bergen S, Ruderfer D . Discovery and statistical genotyping of copy-number variation from whole-exome sequencing depth. Am J Hum Genet. 2012; 91(4):597-607. PMC: 3484655. DOI: 10.1016/j.ajhg.2012.08.005. View

18.

Lee J, Park J, Lee C, Kim A, Kim B, Park W . Genomic Analysis of Korean Patient With Microcephaly. Front Genet. 2021; 11:543528. PMC: 7876370. DOI: 10.3389/fgene.2020.543528. View

19.

Duerinckx S, Desir J, Perazzolo C, Badoer C, Jacquemin V, Soblet J . Phenotypes and genotypes in non-consanguineous and consanguineous primary microcephaly: High incidence of epilepsy. Mol Genet Genomic Med. 2021; 9(9):e1768. PMC: 8457702. DOI: 10.1002/mgg3.1768. View

20.

Naslavsky M, Yamamoto G, Almeida T, Ezquina S, Sunaga D, Pho N . Exomic variants of an elderly cohort of Brazilians in the ABraOM database. Hum Mutat. 2017; 38(7):751-763. DOI: 10.1002/humu.23220. View