%0 Journal Article %J Hum Mol Genet %D 2021 %T NMIHBA results from hypomorphic PRUNE1 variants that lack short-chain exopolyphosphatase activity. %A Nistala, Harikiran %A Dronzek, John %A Gonzaga-Jauregui, Claudia %A Chim, Shek Man %A Rajamani, Saathyaki %A Nuwayhid, Samer %A Delgado, Dennis %A Burke, Elizabeth %A Karaca, Ender %A Franklin, Matthew C %A Sarangapani, Prasad %A Podgorski, Michael %A Tang, Yajun %A Dominguez, Melissa G %A Withers, Marjorie %A Deckelbaum, Ron A %A Scheonherr, Christopher J %A Gahl, William A %A Malicdan, May C %A Zambrowicz, Brian %A Gale, Nicholas W %A Richard A Gibbs %A Chung, Wendy K %A James R Lupski %A Economides, Aris N %K Acid Anhydride Hydrolases %K Alleles %K Animals %K Child, Preschool %K Female %K Humans %K Infant %K Intellectual Disability %K Male %K Mice %K Microcephaly %K Muscle Hypotonia %K Mutation %K Neurodevelopmental Disorders %K Pedigree %K Phenotype %K Phosphoric Monoester Hydrolases %X

Neurodevelopmental disorder with microcephaly, hypotonia and variable brain anomalies (NMIHBA) is an autosomal recessive neurodevelopmental and neurodegenerative disorder characterized by global developmental delay and severe intellectual disability. Microcephaly, progressive cortical atrophy, cerebellar hypoplasia and delayed myelination are neurological hallmarks in affected individuals. NMIHBA is caused by biallelic variants in PRUNE1 encoding prune exopolyphosphatase 1. We provide in-depth clinical description of two affected siblings harboring compound heterozygous variant alleles, c.383G > A (p.Arg128Gln), c.520G > T (p.Gly174*) in PRUNE1. To gain insights into disease biology, we biochemically characterized missense variants within the conserved N-terminal aspartic acid-histidine-histidine (DHH) motif and provide evidence that they result in the destabilization of protein structure and/or loss of exopolyphosphatase activity. Genetic ablation of Prune1 results in midgestational lethality in mice, associated with perturbations to embryonic growth and vascular development. Our findings suggest that NMIHBA results from hypomorphic variant alleles in humans and underscore the potential key role of PRUNE1 exopolyphoshatase activity in neurodevelopment.

%B Hum Mol Genet %V 29 %P 3516-3531 %8 2021 Jan 06 %G eng %N 21 %1 https://www.ncbi.nlm.nih.gov/pubmed/33105479?dopt=Abstract %R 10.1093/hmg/ddaa237 %0 Journal Article %J Eur J Hum Genet %D 2020 %T Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide. %A Gonzaga-Jauregui, Claudia %A Yesil, Gozde %A Nistala, Harikiran %A Gezdirici, Alper %A Bayram, Yavuz %A Nannuru, Kalyan C %A Pehlivan, Davut %A Bo Yuan %A Jimenez, Johanna %A Sahin, Yavuz %A Paine, Ingrid S %A Akdemir, Zeynep Coban %A Rajamani, Saathyaki %A Staples, Jeffrey %A Dronzek, John %A Howell, Kristen %A Fatih, Jawid M %A Smaldone, Silvia %A Schlesinger, Alan E %A Ramírez, Norman %A Cornier, Alberto S %A Kelly, Melissa A %A Haber, Robert %A Chim, Shek Man %A Nieman, Kristy %A Wu, Nan %A Walls, Johnathon %A Poueymirou, William %A Siao, Chia-Jen %A Sutton, V Reid %A Williams, Marc S %A Posey, Jennifer E %A Richard A Gibbs %A Carlo, Simon %A Tegay, David H %A Economides, Aris N %A James R Lupski %K Abnormalities, Multiple %K Adolescent %K Animals %K Bone Development %K Child %K Child, Preschool %K Consanguinity %K Extracellular Matrix %K Female %K Fibrillar Collagens %K Founder Effect %K Gene Frequency %K Hip Dislocation %K Homozygote %K Humans %K Male %K Mice %K Mice, Inbred C57BL %K Mutation %K Pedigree %K Scoliosis %K Syndrome %X

Previously we reported the identification of a homozygous COL27A1 (c.2089G>C; p.Gly697Arg) missense variant and proposed it as a founder allele in Puerto Rico segregating with Steel syndrome (STLS, MIM #615155); a rare osteochondrodysplasia characterized by short stature, congenital bilateral hip dysplasia, carpal coalitions, and scoliosis. We now report segregation of this variant in five probands from the initial clinical report defining the syndrome and an additional family of Puerto Rican descent with multiple affected adult individuals. We modeled the orthologous variant in murine Col27a1 and found it recapitulates some of the major Steel syndrome associated skeletal features including reduced body length, scoliosis, and a more rounded skull shape. Characterization of the in vivo murine model shows abnormal collagen deposition in the extracellular matrix and disorganization of the proliferative zone of the growth plate. We report additional COL27A1 pathogenic variant alleles identified in unrelated consanguineous Turkish kindreds suggesting Clan Genomics and identity-by-descent homozygosity contributing to disease in this population. The hypothesis that carrier states for this autosomal recessive osteochondrodysplasia may contribute to common complex traits is further explored in a large clinical population cohort. Our findings augment our understanding of COL27A1 biology and its role in skeletal development; and expand the functional allelic architecture in this gene underlying both rare and common disease phenotypes.

%B Eur J Hum Genet %V 28 %P 1243-1264 %8 2020 Sep %G eng %N 9 %1 https://www.ncbi.nlm.nih.gov/pubmed/32376988?dopt=Abstract %R 10.1038/s41431-020-0632-x %0 Journal Article %J Cold Spring Harb Mol Case Stud %D 2017 %T An exome sequencing study of Moebius syndrome including atypical cases reveals an individual with CFEOM3A and a mutation. %A Patel, Ronak M %A Liu, David %A Gonzaga-Jauregui, Claudia %A Jhangiani, Shalini %A Lu, James T %A Sutton, V Reid %A Fernbach, Susan D %A Azamian, Mahshid %A White, Lisa %A Edmond, Jane C %A Paysse, Evelyn A %A Belmont, John W %A Muzny, Donna %A Lupski, James R %A Gibbs, Richard A %A Lewis, Richard Alan %A Lee, Brendan H %A Lalani, Seema R %A Campeau, Philippe M %K Child %K Child, Preschool %K Cohort Studies %K Exome %K Exome Sequencing %K Eye Diseases, Hereditary %K Facial Paralysis %K Female %K Humans %K Infant %K Male %K Malformations of Cortical Development %K Mobius Syndrome %K Muscular Diseases %K Mutation %K Ocular Motility Disorders %K Ophthalmoplegia %K Orbital Diseases %K Pedigree %K Tubulin %X

Moebius syndrome is characterized by congenital unilateral or bilateral facial and abducens nerve palsies (sixth and seventh cranial nerves) causing facial weakness, feeding difficulties, and restricted ocular movements. Abnormalities of the chest wall such as Poland anomaly and variable limb defects are frequently associated with this syndrome. Most cases are isolated; however, rare families with autosomal dominant transmission with incomplete penetrance and variable expressivity have been described. The genetic basis of this condition remains unknown. In a cohort study of nine individuals suspected to have Moebius syndrome (six typical, three atypical), we performed whole-exome sequencing to try to identify a commonly mutated gene. Although no such gene was identified and we did not find mutations in and , we found a de novo heterozygous mutation, p.E410K, in the gene encoding tubulin beta 3 class III (), in an individual with atypical Moebius syndrome. This individual was diagnosed with near-complete ophthalmoplegia, agenesis of the corpus callosum, and absence of the septum pellucidum. No substantial limb abnormalities were noted. Mutations in have been associated with complex cortical dysplasia and other brain malformations and congenital fibrosis of extraocular muscles type 3A (CFEOM3A). Our report highlights the overlap of genetic etiology and clinical differences between CFEOM and Moebius syndrome and describes our approach to identifying candidate genes for typical and atypical Moebius syndrome.

%B Cold Spring Harb Mol Case Stud %V 3 %P a000984 %8 2017 Mar %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/28299356?dopt=Abstract %R 10.1101/mcs.a000984 %0 Journal Article %J Cell %D 2017 %T An Organismal CNV Mutator Phenotype Restricted to Early Human Development. %A Liu, Pengfei %A Yuan, Bo %A Carvalho, Claudia M B %A Wuster, Arthur %A Walter, Klaudia %A Zhang, Ling %A Gambin, Tomasz %A Chong, Zechen %A Campbell, Ian M %A Coban Akdemir, Zeynep %A Gelowani, Violet %A Writzl, Karin %A Bacino, Carlos A %A Lindsay, Sarah J %A Withers, Marjorie %A Gonzaga-Jauregui, Claudia %A Wiszniewska, Joanna %A Scull, Jennifer %A Stankiewicz, Paweł %A Jhangiani, Shalini N %A Muzny, Donna M %A Zhang, Feng %A Chen, Ken %A Gibbs, Richard A %A Rautenstrauss, Bernd %A Cheung, Sau Wai %A Smith, Janice %A Breman, Amy %A Shaw, Chad A %A Patel, Ankita %A Hurles, Matthew E %A Lupski, James R %K Chromosome Aberrations %K Chromosome Breakpoints %K Chromosome Duplication %K DNA Copy Number Variations %K DNA Replication %K Embryonic Development %K Female %K Gametogenesis %K Genetic Diseases, Inborn %K Genomic Instability %K Humans %K Male %K Mutation %X

De novo copy number variants (dnCNVs) arising at multiple loci in a personal genome have usually been considered to reflect cancer somatic genomic instabilities. We describe a multiple dnCNV (MdnCNV) phenomenon in which individuals with genomic disorders carry five to ten constitutional dnCNVs. These CNVs originate from independent formation incidences, are predominantly tandem duplications or complex gains, exhibit breakpoint junction features reminiscent of replicative repair, and show increased de novo point mutations flanking the rearrangement junctions. The active CNV mutation shower appears to be restricted to a transient perizygotic period. We propose that a defect in the CNV formation process is responsible for the "CNV-mutator state," and this state is dampened after early embryogenesis. The constitutional MdnCNV phenomenon resembles chromosomal instability in various cancers. Investigations of this phenomenon may provide unique access to understanding genomic disorders, structural variant mutagenesis, human evolution, and cancer biology.

%B Cell %V 168 %P 830-842.e7 %8 2017 Feb 23 %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/28235197?dopt=Abstract %R 10.1016/j.cell.2017.01.037 %0 Journal Article %J Cell Rep %D 2015 %T Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy. %A Gonzaga-Jauregui, Claudia %A Harel, Tamar %A Gambin, Tomasz %A Kousi, Maria %A Griffin, Laurie B %A Francescatto, Ludmila %A Ozes, Burcak %A Karaca, Ender %A Jhangiani, Shalini N %A Bainbridge, Matthew N %A Lawson, Kim S %A Pehlivan, Davut %A Okamoto, Yuji %A Withers, Marjorie %A Mancias, Pedro %A Slavotinek, Anne %A Reitnauer, Pamela J %A Goksungur, Meryem T %A Shy, Michael %A Crawford, Thomas O %A Koenig, Michel %A Willer, Jason %A Flores, Brittany N %A Pediaditrakis, Igor %A Us, Onder %A Wiszniewski, Wojciech %A Parman, Yesim %A Antonellis, Anthony %A Muzny, Donna M %A Katsanis, Nicholas %A Battaloglu, Esra %A Boerwinkle, Eric %A Gibbs, Richard A %A Lupski, James R %K Animals %K Charcot-Marie-Tooth Disease %K Exome %K Female %K Genetic Load %K Genetic Variation %K HSP40 Heat-Shock Proteins %K Humans %K Male %K Mutation %K Myelin P2 Protein %K Pedigree %K Penetrance %K Peripheral Nervous System Diseases %K Phenotype %K Serine C-Palmitoyltransferase %K Suppression, Genetic %K Zebrafish %X

Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous distal symmetric polyneuropathy. Whole-exome sequencing (WES) of 40 individuals from 37 unrelated families with CMT-like peripheral neuropathy refractory to molecular diagnosis identified apparent causal mutations in ∼ 45% (17/37) of families. Three candidate disease genes are proposed, supported by a combination of genetic and in vivo studies. Aggregate analysis of mutation data revealed a significantly increased number of rare variants across 58 neuropathy-associated genes in subjects versus controls, confirmed in a second ethnically discrete neuropathy cohort, suggesting that mutation burden potentially contributes to phenotypic variability. Neuropathy genes shown to have highly penetrant Mendelizing variants (HPMVs) and implicated by burden in families were shown to interact genetically in a zebrafish assay exacerbating the phenotype established by the suppression of single genes. Our findings suggest that the combinatorial effect of rare variants contributes to disease burden and variable expressivity.

%B Cell Rep %V 12 %P 1169-83 %8 2015 Aug 18 %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/26257172?dopt=Abstract %R 10.1016/j.celrep.2015.07.023 %0 Journal Article %J Eur J Hum Genet %D 2015 %T Mutations in COL27A1 cause Steel syndrome and suggest a founder mutation effect in the Puerto Rican population. %A Gonzaga-Jauregui, Claudia %A Gamble, Candace N %A Yuan, Bo %A Penney, Samantha %A Jhangiani, Shalini %A Muzny, Donna M %A Gibbs, Richard A %A Lupski, James R %A Hecht, Jacqueline T %K Amino Acid Sequence %K Child, Preschool %K Comparative Genomic Hybridization %K Exome %K Female %K Fibrillar Collagens %K Follow-Up Studies %K Founder Effect %K Genotype %K Hispanic or Latino %K Humans %K Infant %K Male %K Molecular Sequence Data %K Mutation %K Osteochondrodysplasias %K Pedigree %K Polymorphism, Single Nucleotide %K Prostaglandins F %K Puerto Rico %K Sequence Alignment %X

Osteochondrodysplasias represent a large group of developmental structural disorders that can be caused by mutations in a variety of genes responsible for chondrocyte development, differentiation, mineralization and early ossification. The application of whole-exome sequencing to disorders apparently segregating as Mendelian traits has proven to be an effective approach to disease gene identification for conditions with unknown molecular etiology. We identified a homozygous missense variant p.(Gly697Arg) in COL27A1, in a family with Steel syndrome and no consanguinity. Interestingly, the identified variant seems to have arisen as a founder mutation in the Puerto Rican population.

%B Eur J Hum Genet %V 23 %P 342-6 %8 2015 Mar %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/24986830?dopt=Abstract %R 10.1038/ejhg.2014.107 %0 Journal Article %J Genet Med %D 2014 %T Exonic duplication CNV of NDRG1 associated with autosomal-recessive HMSN-Lom/CMT4D. %A Okamoto, Yuji %A Goksungur, Meryem Tuba %A Pehlivan, Davut %A Beck, Christine R %A Gonzaga-Jauregui, Claudia %A Muzny, Donna M %A Atik, Mehmed M %A Carvalho, Claudia M B %A Matur, Zeliha %A Bayraktar, Serife %A Boone, Philip M %A Akyuz, Kaya %A Gibbs, Richard A %A Battaloglu, Esra %A Parman, Yesim %A Lupski, James R %K Adult %K Base Sequence %K Cell Cycle Proteins %K Charcot-Marie-Tooth Disease %K Comparative Genomic Hybridization %K DNA Copy Number Variations %K Female %K Gene Duplication %K Gene Expression %K Genes, Recessive %K Humans %K Intracellular Signaling Peptides and Proteins %K Male %K Mutation %K Refsum Disease %K Sequence Analysis, DNA %K Turkey %K Young Adult %X

PURPOSE: Copy-number variations as a mutational mechanism contribute significantly to human disease. Approximately one-half of the patients with Charcot-Marie-Tooth (CMT) disease have a 1.4 Mb duplication copy-number variation as the cause of their neuropathy. However, non-CMT1A neuropathy patients rarely have causative copy-number variations, and to date, autosomal-recessive disease has not been associated with copy-number variation as a mutational mechanism.

METHODS: We performed Agilent 8 × 60 K array comparative genomic hybridization on DNA from 12 recessive Turkish families with CMT disease. Additional molecular studies were conducted to detect breakpoint junctions and to evaluate gene expression levels in a family in which we detected an intragenic duplication copy-number variation.

RESULTS: We detected an ~6.25 kb homozygous intragenic duplication in NDRG1, a gene known to be causative for recessive HMSNL/CMT4D, in three individuals from a Turkish family with CMT neuropathy. Further studies showed that this intragenic copy-number variation resulted in a homozygous duplication of exons 6-8 that caused decreased mRNA expression of NDRG1.

CONCLUSION: Exon-focused high-resolution array comparative genomic hybridization enables the detection of copy-number variation carrier states in recessive genes, particularly small copy-number variations encompassing or disrupting single genes. In families for whom a molecular diagnosis has not been elucidated by conventional clinical assays, an assessment for copy-number variations in known CMT genes might be considered.

%B Genet Med %V 16 %P 386-394 %8 2014 May %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/24136616?dopt=Abstract %R 10.1038/gim.2013.155 %0 Journal Article %J PLoS Genet %D 2014 %T Heterozygous de novo and inherited mutations in the smooth muscle actin (ACTG2) gene underlie megacystis-microcolon-intestinal hypoperistalsis syndrome. %A Wangler, Michael F %A Gonzaga-Jauregui, Claudia %A Gambin, Tomasz %A Penney, Samantha %A Moss, Timothy %A Chopra, Atul %A Probst, Frank J %A Xia, Fan %A Yang, Yaping %A Werlin, Steven %A Eglite, Ieva %A Kornejeva, Liene %A Bacino, Carlos A %A Baldridge, Dustin %A Neul, Jeff %A Lehman, Efrat Lev %A Larson, Austin %A Beuten, Joke %A Muzny, Donna M %A Jhangiani, Shalini %A Gibbs, Richard A %A Lupski, James R %A Beaudet, Arthur %K Abnormalities, Multiple %K Actins %K Adolescent %K Adult %K Child %K Child, Preschool %K Colon %K Exome %K Female %K Heterozygote %K Humans %K Intestinal Pseudo-Obstruction %K Male %K Muscle, Smooth %K Mutation %K Urinary Bladder %X

Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is a rare disorder of enteric smooth muscle function affecting the intestine and bladder. Patients with this severe phenotype are dependent on total parenteral nutrition and urinary catheterization. The cause of this syndrome has remained a mystery since Berdon's initial description in 1976. No genes have been clearly linked to MMIHS. We used whole-exome sequencing for gene discovery followed by targeted Sanger sequencing in a cohort of patients with MMIHS and intestinal pseudo-obstruction. We identified heterozygous ACTG2 missense variants in 15 unrelated subjects, ten being apparent de novo mutations. Ten unique variants were detected, of which six affected CpG dinucleotides and resulted in missense mutations at arginine residues, perhaps related to biased usage of CpG containing codons within actin genes. We also found some of the same heterozygous mutations that we observed as apparent de novo mutations in MMIHS segregating in families with intestinal pseudo-obstruction, suggesting that ACTG2 is responsible for a spectrum of smooth muscle disease. ACTG2 encodes γ2 enteric actin and is the first gene to be clearly associated with MMIHS, suggesting an important role for contractile proteins in enteric smooth muscle disease.

%B PLoS Genet %V 10 %P e1004258 %8 2014 Mar %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/24676022?dopt=Abstract %R 10.1371/journal.pgen.1004258 %0 Journal Article %J Am J Med Genet A %D 2014 %T Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome. %A Bayram, Yavuz %A Pehlivan, Davut %A Karaca, Ender %A Gambin, Tomasz %A Jhangiani, Shalini N %A Erdin, Serkan %A Gonzaga-Jauregui, Claudia %A Wiszniewski, Wojciech %A Muzny, Donna %A Elcioglu, Nursel H %A Yildirim, M Selman %A Bozkurt, Banu %A Zamani, Ayse Gul %A Boerwinkle, Eric %A Gibbs, Richard A %A Lupski, James R %K Adolescent %K Adult %K Alopecia %K Anodontia %K Base Sequence %K Child %K Chromosome Segregation %K DNA Mutational Analysis %K Exome %K Facies %K Family %K Female %K Growth Disorders %K Humans %K Male %K Microfilament Proteins %K Molecular Sequence Data %K Mutation %K Neoplasm Proteins %K Optic Atrophies, Hereditary %K Pedigree %K Protein Structure, Tertiary %K Receptors, Cell Surface %X

GAPO syndrome (OMIM#230740) is the acronym for growth retardation, alopecia, pseudoanodontia, and optic atrophy. About 35 cases have been reported, making it among one of the rarest recessive conditions. Distinctive craniofacial features including alopecia, rarefaction of eyebrows and eyelashes, frontal bossing, high forehead, mid-facial hypoplasia, hypertelorism, and thickened eyelids and lips make GAPO syndrome a clinically recognizable phenotype. While this genomic study was in progress mutations in ANTXR1 were reported to cause GAPO syndrome. In our study we performed whole exome sequencing (WES) for five affected individuals from three Turkish kindreds segregating the GAPO trait. Exome sequencing analysis identified three novel homozygous mutations including; one frame-shift (c.1220_1221insT; p.Ala408Cysfs*2), one splice site (c.411A>G; p.Gln137Gln), and one non-synonymous (c.1150G>A; p.Gly384Ser) mutation in the ANTXR1 gene. Our studies expand the allelic spectrum in this rare condition and potentially provide insight into the role of ANTXR1 in the regulation of the extracellular matrix.

%B Am J Med Genet A %V 164A %P 2328-34 %8 2014 Sep %G eng %N 9 %1 https://www.ncbi.nlm.nih.gov/pubmed/25045128?dopt=Abstract %R 10.1002/ajmg.a.36678 %0 Journal Article %J JAMA Neurol %D 2013 %T Mutations in VRK1 associated with complex motor and sensory axonal neuropathy plus microcephaly. %A Gonzaga-Jauregui, Claudia %A Lotze, Timothy %A Jamal, Leila %A Penney, Samantha %A Campbell, Ian M %A Pehlivan, Davut %A Hunter, Jill V %A Woodbury, Suzanne L %A Raymond, Gerald %A Adesina, Adekunle M %A Jhangiani, Shalini N %A Reid, Jeffrey G %A Muzny, Donna M %A Boerwinkle, Eric %A Lupski, James R %A Gibbs, Richard A %A Wiszniewski, Wojciech %K Child %K Child, Preschool %K DNA Mutational Analysis %K Female %K Genotype %K Hereditary Sensory and Motor Neuropathy %K Humans %K Infant %K Intracellular Signaling Peptides and Proteins %K Magnetic Resonance Imaging %K Male %K Microcephaly %K Mutation %K Neural Conduction %K Polymorphism, Single Nucleotide %K Protein Serine-Threonine Kinases %X

IMPORTANCE: Patients with rare diseases and complex clinical presentations represent a challenge for clinical diagnostics. Genomic approaches are allowing the identification of novel variants in genes for very rare disorders, enabling a molecular diagnosis. Genomics is also revealing a phenotypic expansion whereby the full spectrum of clinical expression conveyed by mutant alleles at a locus can be better appreciated.

OBJECTIVE: To elucidate the molecular cause of a complex neuropathy phenotype in 3 patients by applying genomic sequencing strategies.

DESIGN, SETTING, AND PARTICIPANTS: Three affected individuals from 2 unrelated families presented with a complex neuropathy phenotype characterized by axonal sensorimotor neuropathy and microcephaly. They were recruited into the Centers for Mendelian Genomics research program to identify the molecular cause of their phenotype. Whole-genome, targeted whole-exome sequencing, and high-resolution single-nucleotide polymorphism arrays were performed in genetics clinics of tertiary care pediatric hospitals and biomedical research institutions.

MAIN OUTCOMES AND MEASURES: Whole-genome and whole-exome sequencing identified the variants responsible for the patients' clinical phenotype.

RESULTS: We identified compound heterozygous alleles in 2 affected siblings from 1 family and a homozygous nonsense variant in the third unrelated patient in the vaccinia-related kinase 1 gene (VRK1). In the latter subject, we found a common haplotype on which the nonsense mutation occurred and that segregates in the Ashkenazi Jewish population.

CONCLUSIONS AND RELEVANCE: We report the identification of disease-causing alleles in 3 children from 2 unrelated families with a previously uncharacterized complex axonal motor and sensory neuropathy accompanied by severe nonprogressive microcephaly and cerebral dysgenesis. Our data raise the question of whether VRK1 mutations disturb cell cycle progression and may result in apoptosis of cells in the nervous system. The application of unbiased genomic approaches allows the identification of potentially pathogenic mutations in unsuspected genes in highly genetically heterogeneous and uncharacterized neurological diseases.

%B JAMA Neurol %V 70 %P 1491-8 %8 2013 Dec %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/24126608?dopt=Abstract %R 10.1001/jamaneurol.2013.4598