Gorlin-chaudhry-moss syndrome revisited: Expanding the phenotype

Gorlin-Chaudhry-Moss syndrome (OMIM 233500) is a rare congenital malformation syndrome with the cardinal manifestations of craniofacial dysostosis, hypertrichosis, underdeveloped genitalia, ocular, and dental anomalies. Since 1960, only six affected individuals have been reported. We report a 4-year and 6-month-old female patient with this phenotype and review the clinical presentation of all patients known so far. Previously unreported malformations of the extremities, larynx, and nose are also described, expanding the phenotype of this rare syndrome. Array-CGH analysis did not show pathological deletions or duplications. (c) 2013 Wiley Periodicals, Inc

Gorlin-chaudhry-moss syndrome revisited: Expanding the phenotype

Gorlin-Chaudhry-Moss syndrome (OMIM 233500) is a rare congenital malformation syndrome with the cardinal manifestations of craniofacial dysostosis, hypertrichosis, underdeveloped genitalia, ocular, and dental anomalies. Since 1960, only six affected individuals have been reported. We report a 4-year and 6-month-old female patient with this phenotype and review the clinical presentation of all patients known so far. Previously unreported malformations of the extremities, larynx, and nose are also described, expanding the phenotype of this rare syndrome. Array-CGH analysis did not show pathological deletions or duplications. (c) 2013 Wiley Periodicals, Inc

Mutations in MBOAT7, Encoding Lysophosphatidylinositol Acyltransferase I, Lead to Intellectual Disability Accompanied by Epilepsy and Autistic Features

WOS: 000385333700011PubMed ID: 27616480The risk of epilepsy among individuals with intellectual disability (ID) is approximately ten times that of the general population. From a cohort of >5,000 families affected by neurodevelopmental disorders, we identified six consanguineous families harboring homozygous inactivating variants in MBOAT7, encoding lysophosphatidylinositol acyltransferase (LPIAT1). Subjects presented with ID frequently accompanied by epilepsy and autistic features. LPIAT1 is a membrane-bound phospholipid-remodeling enzyme that transfers arachidonic acid (AA) to lysophosphatidylinositol to produce AA-containing phosphatidylinositol. This study suggests a role for AA-containing phosphatidylinositols in the development of ID accompanied by epilepsy and autistic features.Howard Hughes Medical Institute; National Institute of Neurological Disorders and Stroke [R01NS098004, R01NS048453]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [P01HD070494]; Qatar National Research Fund [NPRP6-1463]; Simons Foundation Autism Research Initiative [175303, 275275]; Deutsche Forschungsgemeinschaft (DFG) [AB393/2-2, AB393/4-1]; Canadian Institutes of Health Research [MOP-102758]; Pakistani Higher Education CommissionWe are grateful to the affected individuals and their families for their participation in the study. This study was supported by the Howard Hughes Medical Institute, National Institute of Neurological Disorders and Stroke (R01NS098004 and R01NS048453), Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01HD070494), Qatar National Research Fund (NPRP6-1463), and Simons Foundation Autism Research Initiative (175303 and 275275). We thank the Broad Institute (U54HG003067 to E. Lander and HG00 8900 to D. MacArthur) and the Yale Center for Mendelian Disorders (U54HG006504 to R. Lifton, M. Gunel, M. Gerstein, and S. Mane) for sequencing support and analysis. This study was partially supported by grants from the Deutsche Forschungsgemeinschaft (DFG) to R.A.J. (AB393/2-2 and AB393/4-1), a grant from the Canadian Institutes of Health Research to J.B.V. (MOP-102758), and an award from the Pakistani Higher Education Commission to I.A

Loss of NARS1 impairs progenitor proliferation in cortical brain organoids and leads to microcephaly

Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Here, we identify biallelic missense and frameshift mutations in NARS1 in seven patients from three unrelated families with microcephaly and neurodevelopmental delay. Patient cells show reduced NARS1 protein, impaired NARS1 activity and impaired global protein synthesis. Cortical brain organoid modeling shows reduced proliferation of radial glial cells (RGCs), leading to smaller organoids characteristic of microcephaly. Single-cell analysis reveals altered constituents of both astrocytic and RGC lineages, suggesting a requirement for NARS1 in RGC proliferation. Our findings demonstrate that NARS1 is required to meet protein synthetic needs and to support RGC proliferation in human brain development

Autosomal-Recessive Mutations in the tRNA Splicing Endonuclease Subunit TSEN15 Cause Pontocerebellar Hypoplasia and Progressive Microcephaly

The tRNA splicing endonuclease is a highly evolutionarily conserved protein complex, involved in the cleavage of intron-containing tRNAs. In human it consists of the catalytic subunits TSEN2 and TSEN34, as well as the non-catalytic TSEN54 and TSEN15. Recessive mutations in the corresponding genes of the first three are known to cause pontocerebellar hypoplasia (PCH) types 2A-C, 4, and 5. Here, we report three homozygous TSEN15 variants that cause a milder version of PCH2. The affected individuals showed progressive microcephaly, delayed developmental milestones, intellectual disability, and, in two out of four cases, epilepsy. None, however, displayed the central visual failure seen in PCH case subjects where other subunits of the TSEN are mutated, and only one was affected by the extensive motor defects that are typical in other forms of PCH2. The three amino acid substitutions impacted the protein level of TSEN15 and the stoichiometry of the interacting subunits in different ways, but all resulted in an almost complete loss of in vitro tRNA cleavage activity. Taken together, our results demonstrate that mutations in any known subunit of the TSEN complex can cause PCH and progressive microcephaly, emphasizing the importance of its function during brain development

Author Correction: Loss of NARS1 impairs progenitor proliferation in cortical brain organoids and leads to microcephaly (Nature Communications, (2020), 11, 1, (4038), 10.1038/s41467-020-17454-4)

The original version of this Article omitted a reference to another publication which included overlapping genetic and MRI data for a research participant. This has been added as reference 59 at the end of the Discussion: ‘While this paper was under review, a separate paper appeared reporting that mutations in NARS1 associate with neurodevelopmental delay through either biallelic loss or dominant negative effects, impairing NARS1 enzyme activity. This article contained genetic data on family MIC-1433 which overlaps this study59.’ Accordingly, reference 59 has now been included in the References section as ‘Manole, A. et al. De novo and bi-allelic pathogenic variants in NARS1 cause neurodevelopmental delay due to toxic gain-of-function and partial loss-of-function effects. Am. J. Hum. Genet. 107(2), 311–324 (2020).’ In addition, the original version of this Article contained an error in Fig. 1A, where there was an error in the family depiction in generation 1 of pedigree MIC-1433; this has been revised to correctly depict the family. Figure 1D also contained MRI scans that had been previously published in Ref 59; this has been revised to include different and unpublished MRI scans from the same individual. (Figure presented.)

Mutations in MBOAT7, Encoding Lysophosphatidylinositol Acyltransferase I, Lead to Intellectual Disability Accompanied by Epilepsy and Autistic Features

The risk of epilepsy among individuals with intellectual disability (ID) is approximately ten times that of the general population. From a cohort of >5,000 families affected by neurodevelopmental disorders, we identified six consanguineous families harboring homozygous inactivating variants in MBOAT7, encoding lysophosphatidylinositol acyltransferase (LPIAT1). Subjects presented with ID frequently accompanied by epilepsy and autistic features. LPIAT1 is a membrane-bound phospholipid-remodeling enzyme that transfers arachidonic acid (AA) to lysophosphatidylinositol to produce AA-containing phosphatidylinositol. This study suggests a role for AA-containing phosphatidylinositols in the development of ID accompanied by epilepsy and autistic features

Biallelic Mutations in Citron Kinase Link Mitotic Cytokinesis to Human Primary Microcephaly

Cell division terminates with cytokinesis and cellular separation. Autosomal-recessive primary microcephaly (PMCPH) is a neurodevelopmental disorder characterized by a reduction in brain and head size at birth in addition to non-progressive intellectual disability. MCPH is genetically heterogeneous, and 16 loci are known to be associated with loss-of-function mutations predominantly affecting centrosomal-associated proteins, but the multiple roles of centrosomes in cellular function has left questions about etiology. Here, we identified three families affected by homozygous missense mutations in CIT, encoding citron rho-interacting kinase (CIT), which has established roles in cytokinesis. All mutations caused substitution of conserved amino acid residues in the kinase domain and impaired kinase activity. Neural progenitors that were differentiated from induced pluripotent stem cells (iPSCs) derived from individuals with these mutations exhibited abnormal cytokinesis with delayed mitosis, multipolar spindles, and increased apoptosis, rescued by CRISPR/Cas9 genome editing. Our results highlight the importance of cytokinesis in the pathology of primary microcephaly