The Genetics of Primary Microcephaly

Jayaraman, Divya; Bae, Byoung-Il; Walsh, Christopher A.

doi:10.1146/annurev-genom-083117-021441

Cited by 246 publications

(293 citation statements)

References 187 publications

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“…A large number of genes have been associated with isolated primary microcephalies (MCPH: microcephaly primary hereditary), many of which encode proteins with essential roles in chromosomal segregation, mitotic cell division, centrosome, and kinetochore function. Others have a role in DNA damage repair, DNA replication, and cilia function . A distinct group of syndromic disorders with microcephaly are the autosomal recessive microcephalic primordial dwarfisms, which include Seckel syndrome caused by mutations in DNA damage response genes ATR and ATRIP and centriole biogenesis genes.…”

Section: Malformations Of Cortical Developmentmentioning

confidence: 99%

“…Another is Meier‐Gorlin syndrome caused by mutations in ORC1 , ORC4 , ORC6 , and other genes that play a role in origin of DNA replication. A third class of syndromes are the microcephalic osteodysplastic primordial dwarfisms (MOPDs) . These conditions present prenatally with intrauterine growth restriction (IUGR) and microcephaly out of proportion to fetal growth .…”

Section: Malformations Of Cortical Developmentmentioning

confidence: 99%

“…Others have a role in DNA damage repair, DNA replication, and cilia function. [69][70][71] A distinct group of syndromic disorders with microcephaly are the autosomal recessive microcephalic primordial dwarfisms, which include Seckel syndrome caused by mutations in DNA damage response genes ATR and ATRIP and centriole biogenesis genes. Another is Meier-Gorlin syndrome caused by mutations in ORC1, ORC4, ORC6, and other genes that play a role in origin of DNA replication.…”

Section: Genetic Causes Of Microcephaly Include Chromosomal Abnormalimentioning

confidence: 99%

“…A third class of syndromes are the microcephalic osteodysplastic primordial dwarfisms (MOPDs). [69][70][71] These conditions present prenatally with intrauterine growth restriction (IUGR) and microcephaly out of proportion to fetal growth. [69][70][71] MOPD1 is caused by mutations in the noncoding RNA gene…”

Section: Genetic Causes Of Microcephaly Include Chromosomal Abnormalimentioning

confidence: 99%

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Prenatally diagnosed developmental abnormalities of the central nervous system and genetic syndromes: A practical review

Veyver

2019

Prenatal Diagnosis

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Developmental brain abnormalities are complex and can be difficult to diagnose by prenatal imaging because of the ongoing growth and development of the brain throughout pregnancy and the limitations of ultrasound, often requiring fetal magnetic resonance imaging as an additional tool. As for all major structural congenital anomalies, amniocentesis with chromosomal microarray and a karyotype is the first‐line recommended test for the genetic work‐up of prenatally diagnosed central nervous system (CNS) abnormalities. Many CNS defects, especially neuronal migration defects affecting the cerebral and cerebellar cortex, are caused by single‐gene mutations in a large number of different genes. Early data suggest that prenatal diagnostic exome sequencing for fetal CNS defects will have a high diagnostic yield, but interpretation of sequencing results can be complex. Yet a genetic diagnosis is important for prognosis prediction and recurrence risk counseling. The evaluation and management of such patients is best done in a multidisciplinary team approach. Here, we review general principles of the genetic work‐up for fetuses with CNS defects and review categories of genetic causes of prenatally diagnosed CNS phenotypes.

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Section: Malformations Of Cortical Developmentmentioning

confidence: 99%

Section: Malformations Of Cortical Developmentmentioning

confidence: 99%

Section: Genetic Causes Of Microcephaly Include Chromosomal Abnormalimentioning

confidence: 99%

Section: Genetic Causes Of Microcephaly Include Chromosomal Abnormalimentioning

confidence: 99%

See 2 more Smart Citations

Prenatally diagnosed developmental abnormalities of the central nervous system and genetic syndromes: A practical review

Veyver

2019

Prenatal Diagnosis

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“…An integrated table is shown in Table S27. The genes causing primary microcephaly were obtained from the previous study (Jayaraman, et al 2018). The genes related to adducted thumbs were collected from Human Phenotype Ontology (https://hpo.jax.org/app/ ID: HP:0001181).…”

Section: Identification Of Assvs Related To Ape-specific Traitsmentioning

confidence: 99%

Long-read assembly of the Chinese rhesus macaque genome and identification of ape-specific structural variants

Luo

Zhou

et al. 2019

Preprint

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Rhesus macaque (Macaca mulatta) is a widely-studied nonhuman primate. Here we present a high-quality de novo genome assembly of the Chinese rhesus macaque (rheMacS) using long-read sequencing and multiplatform scaffolding approaches.Compared to the current Indian rhesus macaque reference genome (rheMac8), the rheMacS genome assembly improves sequence contiguity by 75-fold, closing 21,940 of the remaining assembly gaps (60.8 Mbp). To improve gene annotation, we generated more than two million full-length transcripts from ten different tissues by long-read RNA sequencing. We sequence resolve 53,916 structural variants (96% novel) and identify 17,000 ape-specific structural variants (ASSVs) based on comparison to the long-read assembly of ape genomes. We show that many ASSVs map within ChIP-seq predicted enhancer regions where apes and macaque show diverged enhancer activity and gene expression. We further characterize a set of candidate ASSVs that may contribute to ape-or great-ape-specific phenotypic traits, including taillessness, brain volume expansion, improved manual dexterity, and large body size. This improved rheMacS genome assembly serves as an ideal reference for future biomedical and evolutionary studies.

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Adaptive Evolution of Microcephaly Genes

Montgomery

2019

Encyclopedia of Life Sciences

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The human brain is dramatically enlarged compared to our closest relatives. Brain expansion is closely linked to the evolution of complex behaviour and cognition in hominins. Identifying the genetic basis of brain expansion provides one route to understanding what is, and what is not, unique about our species. As part of this approach, researchers have turned to neurodevelopmental disorders for candidate mechanisms. Microcephaly, a disorder characterised by a major and specific underdevelopment of brain size, is a well‐studied example. Genes associated with microcephaly evolved adaptively across both primates and nonprimate mammals, and selection on at least two genes, ASPM and CDK5RAP2 , is associated with variation in brain size in anthropoid primates, and potentially other mammalian clades. While these results support predictions of a model of brain expansion that focuses on cell fate switches during neurogenesis, the causative mechanisms linking selection on microcephaly genes to the evolution brain size remain unclear. Key Concepts Microcephaly (MCPH) is a developmental disorder that results in a severely reduced brain size, defined clinically as a head circumference more than 3 standard deviations below the age/sex mean. MCPH genes are thought to regulate brain growth by affecting key cell fate decisions during neurogenesis. Multiple MCPH genes show signatures of positive selection across primates and across nonprimate mammals. In anthropoid primates (monkeys and apes), the rate of evolution of two MCPH genes, ASPM and CDK5RAP2 , are associated with variation in brain size. Phylogenetic associations are strongest with absolute neonatal brain size, consistent with an evolutionary model where these loci are involved in extending neural proliferation during gestation. Functional test of this evolutionary role remain challenging but several techniques are being developed, including transgenic mice and cerebral organoids.

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The Genetics of Primary Microcephaly

Cited by 246 publications

References 187 publications

Prenatally diagnosed developmental abnormalities of the central nervous system and genetic syndromes: A practical review

Prenatally diagnosed developmental abnormalities of the central nervous system and genetic syndromes: A practical review

Long-read assembly of the Chinese rhesus macaque genome and identification of ape-specific structural variants

Adaptive Evolution of Microcephaly Genes

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