Abstract
Pitt-Hopkins syndrome (PHS) is a rare syndromic encephalopathy characterized by daily bouts of hyperventilation and a facial gestalt. We report a 1.8-Mb de novo microdeletion on chromosome 18q21.1, identified by array-comparative genomic hybridization in one patient with PHS. We subsequently identified two de novo heterozygous missense mutations of a conserved amino acid in the basic region of the TCF4 gene in three additional subjects with PHS. These findings demonstrate that TCF4 anomalies are responsible for PHS and provide the first evidence of a human disorder related to class I basic helix-loop-helix transcription-factor defects (also known as "E proteins"). Moreover, our data may shed new light on the normal processes underlying autonomic nervous system development and maintenance of an appropriate ventilatory neuronal circuitry.
Publication types
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Case Reports
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Autonomic Nervous System Diseases / complications*
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Autonomic Nervous System Diseases / genetics*
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Autonomic Nervous System Diseases / pathology
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Child
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Child, Preschool
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Chromosome Deletion
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Chromosome Mapping
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Chromosomes, Human, Pair 18 / genetics
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DNA-Binding Proteins
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Epilepsy / complications*
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Epilepsy / genetics*
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Epilepsy / pathology
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Female
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Helix-Loop-Helix Motifs / genetics
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Humans
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Magnetic Resonance Imaging
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Male
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Molecular Sequence Data
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Mutation*
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Phenotype
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Sequence Homology, Amino Acid
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Syndrome
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TCF Transcription Factors / genetics*
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Transcription Factor 4
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Transcription Factor 7-Like 2 Protein
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Transcription Factors
Substances
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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DNA-Binding Proteins
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TCF Transcription Factors
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TCF4 protein, human
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TCF7L2 protein, human
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Transcription Factor 4
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Transcription Factor 7-Like 2 Protein
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Transcription Factors
Associated data
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OMIM/602272
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RefSeq/NM_003199