Germline recessive mutations in PI4KA are associated with perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis

Pagnamenta, Alistair T.; Howard, Malcolm F.; Wisniewski, Éva; Popitsch, Niko; Knight, Samantha J. L.; Keays, David A.; Quaghebeur, Gerardine; Cox, Helen; Cox, Phillip; Balla, Tamás; Taylor, Jenny C.; Kini, Usha

doi:10.1093/hmg/ddv117

Cited by 62 publications

(79 citation statements)

References 59 publications

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“…The functional effect of this duplication and the clinical significance is currently unclear. Mutations in PI4KA have recently been linked to an autosomal recessively inherited neuronal migration disorder (Pagnamenta et al., ). Although the family do not have another CNV, the presence of another genetic modifier or a second disorder cannot be excluded, and so further workup is needed to establish the underlying cause for severe features observed in patient 4.…”

Section: Resultsmentioning

confidence: 99%

Atypical nested 22q11.2 duplications between LCR22B and LCR22D are associated with neurodevelopmental phenotypes including autism spectrum disorder with incomplete penetrance

Woodward

Stampalia

Vanyai

et al. 2019

Molec Gen & Gen Med

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Background Chromosome 22q11.2 is susceptible to genomic rearrangements and the most frequently reported involve deletions and duplications between low copy repeats LCR 22A to LCR 22D. Atypical nested deletions and duplications are rarer and can provide a valuable opportunity to investigate the dosage effects of a smaller subset of genes within the 22q11.2 genomic disorder region. Methods We describe thirteen individuals from six families, each with atypical nested duplications within the central 22q11.2 region between LCR 22B and LCR 22D. We then compared the molecular and clinical data for patients from this study and the few reported atypical duplication cases, to the cases with larger typical duplications between LCR 22A and LCR 22D. Further, we analyzed genes with the nested region to identify candidates highly enriched in human brain tissues. Results We observed that atypical nested duplications are heterogeneous in size, often familial, and associated with incomplete penetrance and highly variable clinical expressivity. We found that the nested atypical duplications are a possible risk factor for neurodevelopmental phenotypes, particularly for autism spectrum disorder ( ASD ), speech and language delay, and behavioral abnormalities. In addition, we analyzed genes within the nested region between LCR 22B and LCR 22D to identify nine genes ( ZNF 74, KLHL 22, MED 15, PI 4 KA , SERPIND 1, CRKL , AIFM 3, SLC 7A4, and BCRP 2) with enriched expression in the nervous system, each with unique spatiotemporal patterns in fetal and adult brain tissues. Interestingly, PI 4 KA is prominently expressed in the brain, and this gene is included either partially or completely in all of our subjects. Conclusion Our findings confirm variable expressivity and incomplete penetrance for atypical nested 22q11.2 duplications and identify genes such as PI 4 KA to be directly relevant to brain development and disorder. We conclude that further work is needed to elucidate the basis of variable neurodevelopmental phenotypes and to exclude the presence of a second disorder. Our findings contribute to the genotype–phenotype data for atypical nested 22q11.2 duplications, with implications for genetic counseling.

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Section: Resultsmentioning

confidence: 99%

Atypical nested 22q11.2 duplications between LCR22B and LCR22D are associated with neurodevelopmental phenotypes including autism spectrum disorder with incomplete penetrance

Woodward

Stampalia

Vanyai

et al. 2019

Molec Gen & Gen Med

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“…A list of known genes (Supplemental Table 1) was constructed from multiple online database resources (http:// www.omim.org/, http://www.mnglabs.com/tests/, http://www. ncbi.nlm.nih.gov/pubmed) or abstracted from recently published articles (2,3,(26)(27)(28)(29)(30)(31)(32)(33)(34)(35). Deleterious variants in the known arthrogryposis-associated genes were identified in 17 of 48 (35.4%) unrelated families (Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…In both cases, we also identified potential contributory variants in other known genes ( Table 2). Patient BAB7302 had compound heterozygous mutations in PI4KA, a gene recently associated with brain malformation and arthrogryposis (33). Patient BAB7125 had compound heterozygous variants in MYH14 (Table 2), which encodes a member of the nonmuscle myosin II family of ATP-dependent molecular motors that interact with cytoskeletal actin and regulate cytokinesis, cell motility, and cell polarity (46).…”

Section: L I N I C a L M E D I C I N Ementioning

confidence: 99%

Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin

Bayram

Karaca

Akdemir

et al. 2016

Journal of Clinical Investigation

111

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“…Contingent on local protocol or the presence of pregnancy complications, additional ultrasounds may be performed including a routine evaluation of fetal position, size, and fetal well‐being/biophysical profile in the third trimester. Ultrasound findings associated with AMC during each trimester of pregnancy are detailed in Table …”

Section: Prenatal Evaluation For Arthrogryposis Multiplex Congenitamentioning

confidence: 99%

Fetal arthrogryposis multiplex congenita/fetal akinesia deformation sequence (FADS)—Aetiology, diagnosis, and management

et al. 2019

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Arthrogryposis multiplex congenita (AMC) refers to an aetiologically heterogenous condition, which consists of joint contractures affecting two or more joints starting prenatally. The incidence is approximately one in 3000 live births; however, the prenatal incidence is higher, indicating a high intrauterine mortality. Over 320 genes have been implicated showing the genetic heterogeneity of the condition. AMC can be of extrinsic aetiology resulting from intrauterine crowding secondary to congenital structural uterine abnormalities (eg, bicornuate or septate uterus), uterine tumors (eg, fibroid), or multifetal pregnancy or intrinsic/primary/fetal aetiology, due to functional abnormalities in the brain, spinal cord, peripheral nerves, neuromuscular junction, muscles, bones, restrictive dermopathies, tendons and joints. Unlike many of the intrinsic/primary/fetal causes which are difficult to treat, secondary AMC can be treated by physiotherapy with good response. Primary cases may present prenatally with fetal akinesia associated with joint contractures and occasionally brain abnormalities, decreased muscle bulk, polyhydramnios, and nonvertex presentation while the secondary cases usually present with isolated contractures. Complete prenatal and postnatal investigations are needed to identify an underlying aetiology and provide information regarding its prognosis and inheritance, which is critical for the obstetrical care providers and families to optimize the pregnancy management and address future reproductive plans.

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Germline recessive mutations in PI4KA are associated with perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis

Cited by 62 publications

References 59 publications

Atypical nested 22q11.2 duplications between LCR22B and LCR22D are associated with neurodevelopmental phenotypes including autism spectrum disorder with incomplete penetrance

Atypical nested 22q11.2 duplications between LCR22B and LCR22D are associated with neurodevelopmental phenotypes including autism spectrum disorder with incomplete penetrance

Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin

Fetal arthrogryposis multiplex congenita/fetal akinesia deformation sequence (FADS)—Aetiology, diagnosis, and management

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