22q11.2q13 duplication including SOX10 causes sex-reversal and peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease.
Diagnosis of genetic syndromes may be difficult when specific components of a disorder manifest at a later age. We present a follow up of a previous report [Seeherunvong et al., (2004); AJMGA 127: 149-151], of an individual with 22q duplication and sex-reversal syndrome. The subject's phenotype evolved to include peripheral and central demyelination, Waardenburg syndrome type IV, and Hirschsprung disease (PCWH; MIM 609136). DNA microarray analysis defined the duplication at 22q11.2q13, including SOX10. Sequencing of the coding region of SOX10 did not reveal any mutations. Our data suggest that SOX10 duplication can cause disorders of sex development and PCWH, supporting the hypothesis that SOX10 toxic gain of function rather than dominant negative activity underlies PCWH.
Division of Clinical and Translational Genetics, Dr. John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics Miller School of Medicine, University of Miami and Jackson Memorial Hospital, Miami, Florida.
Nadia
N
Falah
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
Jennifer E
JE
Posey
Division of Clinical and Translational Genetics, Dr. John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics Miller School of Medicine, University of Miami and Jackson Memorial Hospital, Miami, Florida.
Willa
W
Thorson
Memorial HealthCare System, Hollywood, Florida.
Paul
P
Benke
Division of Clinical and Translational Genetics, Dr. John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics Miller School of Medicine, University of Miami and Jackson Memorial Hospital, Miami, Florida.
Mustafa
M
Tekin
Division of Clinical and Translational Genetics, Dr. John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics Miller School of Medicine, University of Miami and Jackson Memorial Hospital, Miami, Florida.
Brocha
B
Tarshish
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.|Department of Pediatrics, Texas Children's Hospital, Houston, Texas.
James R
JR
Lupski
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
Tamar
T
Harel
D058531:46, XX Testicular Disorders of Sex Development; D001741:Black or African American; D058674:Chromosome Duplication; D002892:Chromosomes, Human, Pair 22 / Q000737:chemistry*; D003711:Demyelinating Diseases / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D006627:Hirschsprung Disease / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007676:Kidney Failure, Chronic / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D008297:Male; D020371:Pelizaeus-Merzbacher Disease / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D055757:SOXE Transcription Factors / Q000235:genetics; D014849:Waardenburg Syndrome / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics* / Q000473:pathology
C527923:SOX10 protein, human; D055757:SOXE Transcription Factors
22q duplication syndrome; WS4; Waardenburg syndrome; Waardenburg-Shah syndrome; central demyelinating leukodystrophy; peripheral demyelinating neuropathy