Publications by authors named "Lior Borovik"

3 Publications

  • Page 1 of 1

FOXP1 haploinsufficiency: Phenotypes beyond behavior and intellectual disability?

Am J Med Genet A 2017 Dec 8;173(12):3172-3181. Epub 2017 Sep 8.

Department of Pediatrics, University of South Dakota and Sanford Health, Sioux Falls, South Dakota.

The forkhead box (FOX) transcription factors have roles in development, carcinogenesis, metabolism, and immunity. In humans FOXP1 mutations have been associated with language and speech defects, intellectual disability, autism spectrum disorder, facial dysmorphisms, and congenital anomalies of the kidney and urinary tract. In mice, Foxp1 plays critical roles in development of the spinal motor neurons, lymphocytes, cardiomyocytes, foregut, and skeleton. We hypothesized therefore that mutations of FOXP1 affect additional tissues in some humans. Supporting this hypothesis, we describe two individuals with novel variants of FOXP1 (NM_032682.5:c.975-2A>C and NM_032682.5:c.1574G>A) and additional features. One had a lung disease resembling neuroendocrine cell hyperplasia of infancy (NEHI), and the second had a skeletal disorder with undertubulation of the long bones and relapsing-remitting fevers associated with flushing and edema. Although attribution of these traits to mutation of FOXP1 requires ascertainment of additional patients, we hypothesize that the variable expression of these additional features might arise by means of stochastic developmental variation.
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December 2017

Whole-exome sequencing in the molecular diagnosis of individuals with congenital anomalies of the kidney and urinary tract and identification of a new causative gene.

Genet Med 2017 04 22;19(4):412-420. Epub 2016 Sep 22.

Center for Reproductive Medicine, Baylor College of Medicine, Houston, Texas, USA.

Purpose: To investigate the utility of whole-exome sequencing (WES) to define a molecular diagnosis for patients clinically diagnosed with congenital anomalies of kidney and urinary tract (CAKUT).

Methods: WES was performed in 62 families with CAKUT. WES data were analyzed for single-nucleotide variants (SNVs) in 35 known CAKUT genes, putatively deleterious sequence changes in new candidate genes, and potentially disease-associated copy-number variants (CNVs).

Results: In approximately 5% of families, pathogenic SNVs were identified in PAX2, HNF1B, and EYA1. Observed phenotypes in these families expand the current understanding about the role of these genes in CAKUT. Four pathogenic CNVs were also identified using two CNV detection tools. In addition, we found one deleterious de novo SNV in FOXP1 among the 62 families with CAKUT. The clinical database of the Baylor Miraca Genetics laboratory was queried and seven additional unrelated individuals with novel de novo SNVs in FOXP1 were identified. Six of these eight individuals with FOXP1 SNVs have syndromic urinary tract defects, implicating this gene in urinary tract development.

Conclusion: We conclude that WES can be used to identify molecular etiology (SNVs, CNVs) in a subset of individuals with CAKUT. WES can also help identify novel CAKUT genes.Genet Med 19 4, 412-420.
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April 2017

Pelger-huet anomaly and a mild skeletal phenotype secondary to mutations in LBR.

Am J Med Genet A 2013 Aug 3;161A(8):2066-73. Epub 2013 Jul 3.

Department of Pediatrics, University of Wisconsin-Madison, Madison, WI 53705, USA.

The Lamin B receptor (LBR) gene has been described to encode a bifunctional protein. Mutations in the LBR gene can affect neutrophil segmentation and sterol reductase activity and have been associated with two different recognized clinical conditions, Pelger-Huet anomaly (PHA) and Greenberg skeletal dysplasia. PHA is a benign autosomal co-dominant laminopathy resulting in bilobed neutrophil nuclei in heterozygotes, and unsegmented (ovoid) neutrophil nuclei in homozygotes. Some putative PHA homozygotes have been reported with minor skeletal malformations. Greenberg skeletal dysplasia is a severe autosomal recessive, perinatal lethal dwarfing disorder in which heterozygous carriers are usually without clinical manifestations. We here report a girl who has bilobed neutrophil nuclei and a mild skeletal dysplasia. Mutation analysis showed two novel mutations in the LBR gene: c.651_653 delinsTGATGAGAAA (p.Ile218Aspfs*19) and c.1757G > A (p.Arg586His). These mutations were found to be in trans, and, thus, she is a compound heterozygote. Sterol analysis found trace amounts of cholesta-8,14-dien-3beta-ol, which is normally undetected in healthy individuals. This and previously reported cases suggest that mutations in LBR can result in a continuum of phenotypic manifestations.
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August 2013