Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly

Boonsawat, Paranchai; Joset, Pascal; Steindl, Katharina; Oneda, Beatrice; Gogoll, Laura; Azzarello-Burri, Silvia; Sheth, Frenny; Datar, Chaitanya; Verma, Ishwar C.; Puri, Ratna Dua; Zollino, Marcella; Bachmann‐Gagescu, Ruxandra; Niedrist, Dunja; Papik, Michael; Figueiro-Silva, Joana; Masood, Rahim; Zweier, Christiane; Kraemer, Dennis; Lincoln, Sharyn A.; Rodan, Lance H.; Passemard, Sandrine; Drunat, Séverine; Verloès, Alain; Horn, Anselm H. C.; Sticht, Heinrich; Steinfeld, Robert; Plecko, Barbara; Latal, Beatrice; Jenni, Oskar G.; Asadollahi, Reza; Rauch, Anita

doi:10.1038/s41436-019-0464-7

Cited by 68 publications

(78 citation statements)

References 39 publications

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“…Clinical analysis of these patients was performed during regular consultations focusing on medical history, physical examination, and observational analysis of behavioral features. In all patients, exome sequencing and variant filtering were performed, according to the routine procedures at each institute [17][18][19][20][21][22] .…”

Section: Patientsmentioning

confidence: 99%

Characterization ofSETD1Ahaploinsufficiency in humans andDrosophiladefines a novel neurodevelopmental syndrome

Kummeling

Stremmelaar

Raun

et al. 2019

Preprint

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AbstractDefects in histone methyltransferases (HMTs) are major contributing factors in neurodevelopmental disorders (NDDs). Heterozygous variants of SETD1A involved in histone H3 lysine 4 (H3K4) methylation were previously identified in individuals with schizophrenia. Here, we define the clinical features of the Mendelian syndrome associated with haploinsufficiency of SETD1A by investigating 15 predominantly pediatric individuals who all have de novo SETD1A variants. These individuals present with a core set of symptoms comprising global developmental delay and/or intellectual disability, subtle facial dysmorphisms, behavioral and psychiatric problems. We examined cellular phenotypes in three patient derived lymphoblastoid cell lines with three variants: p.Gly535Alafs*12, c.4582-2_4582delAG, and p.Tyr1499Asp. These patient cell lines displayed DNA damage repair defects that were comparable to previously observed RNAi-mediated depletion of SETD1A. This suggested that these variants, including the p.Tyr1499Asp in the catalytic SET domain, behave as Loss-of-Function (LoF) alleles. Previous studies demonstrated a role for SETD1A in cell cycle control and differentiation. However, individuals with SETD1A variants do not show major structural brain defects or severe microcephaly, suggesting that defective proliferation and differentiation of neural progenitors is unlikely the single underlying cause of the disorder. We show here that the Drosophila Melanogaster SETD1A orthologue is required in postmitotic neurons of the fly brain for normal memory, suggesting a role in post development neuronal function. Together, this study defines a neurodevelopmental disorder caused by dominant de novo LoF variants in SETD1A and further supports a role for H3K4 methyltransferases in the regulation of neuronal processes underlying normal cognitive functioning.

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Section: Patientsmentioning

confidence: 99%

Characterization ofSETD1Ahaploinsufficiency in humans andDrosophiladefines a novel neurodevelopmental syndrome

Kummeling

Stremmelaar

Raun

et al. 2019

Preprint

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“…Although this classification helps managing the differential diagnosis of the patients, it does not reflect underlying mechanisms. Most PMs show autosomal recessive inheritance,1 3 although dominant forms have occasionally been described4–6 and a mitochondrial origin has been proposed 7. To date, >100 genes have been implicated in PM 8…”

Section: Introductionmentioning

confidence: 99%

CDK5RAP2 primary microcephaly is associated with hypothalamic, retinal and cochlear developmental defects

et al. 2020

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BackgroundPrimary hereditary microcephaly (MCPH) comprises a large group of autosomal recessive disorders mainly affecting cortical development and resulting in a congenital impairment of brain growth. Despite the identification of >25 causal genes so far, it remains a challenge to distinguish between different MCPH forms at the clinical level.Methods7 patients with newly identified mutations in CDK5RAP2 (MCPH3) were investigated by performing prospective, extensive and systematic clinical, MRI, psychomotor, neurosensory and cognitive examinations under similar conditions.ResultsAll patients displayed neurosensory defects in addition to microcephaly. Small cochlea with incomplete partition type II was found in all cases and was associated with progressive deafness in 4 of them. Furthermore, the CDK5RAP2 protein was specifically identified in the developing cochlea from human fetal tissues. Microphthalmia was also present in all patients along with retinal pigmentation changes and lipofuscin deposits. Finally, hypothalamic anomalies consisting of interhypothalamic adhesions, a congenital midline defect usually associated with holoprosencephaly, was detected in 5 cases.ConclusionThis is the first report indicating that CDK5RAP2 not only governs brain size but also plays a role in ocular and cochlear development and is necessary for hypothalamic nuclear separation at the midline. Our data indicate that CDK5RAP2 should be considered as a potential gene associated with deafness and forme fruste of holoprosencephaly. These children should be given neurosensory follow-up to prevent additional comorbidities and allow them reaching their full educational potential.Trial registration numberNCT01565005.

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“…Multiple genes harbor biallelic pathogenic variants causing MCPH, with many of them encoding centrosomal proteins involved in early processes like neurogenesis. Depending on the causative gene, the phenotype can vary by severity or involve additional features (Boonsawat et al, ). The spectrum of MCPH continues to expand as additional genes are uncovered, and CEP55 should likely be added to this list.…”

Section: Discussionmentioning

confidence: 99%

Expanding the spectrum of CEP55‐associated disease to viable phenotypes

Barrie

Overwater

Haelst

et al. 2020

American J of Med Genetics Pt A

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Homozygosity for nonsense variants in CEP55 has been associated with a lethal condition characterized by multinucleated neurons, anhydramnios, renal dysplasia, cerebellar hypoplasia, and hydranencephaly (MARCH syndrome) also known as Meckel-like syndrome. Missense variants in CEP55 have not previously been reported in association with disease. Here we describe seven living individuals from five families with biallelic CEP55 variants. Four unrelated individuals with microcephaly, speech delays, and bilateral toe syndactyly all have a common CEP55 variant c.70G>A p.(Glu24Lys) in trans with nonsense variants. Three siblings are homozygous for a consensus splice site variant near the end of the gene. These affected girls all have severely delayed development, microcephaly, and varying degrees of lissencephaly/pachygyria. Here we compare our seven patients with three previously reported families with a prenatal lethal phenotype (MARCH syndrome/Meckel-like syndrome) due to homozygous CEP55 nonsense variants. Our series suggests that individuals with compound heterozygosity for nonsense and missense variants in

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Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly

Cited by 68 publications

References 39 publications

Characterization ofSETD1Ahaploinsufficiency in humans andDrosophiladefines a novel neurodevelopmental syndrome

Characterization ofSETD1Ahaploinsufficiency in humans andDrosophiladefines a novel neurodevelopmental syndrome

CDK5RAP2 primary microcephaly is associated with hypothalamic, retinal and cochlear developmental defects

Expanding the spectrum of CEP55‐associated disease to viable phenotypes

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