Further delineation of Pitt-Hopkins syndrome: phenotypic and genotypic description of sixteen novel patients

Christiane Zweier ¹, Heinrich Sticht ², Emilia Bijlsma ³, Jill Clayton-Smith ⁴, Susanne E Boonen ⁵, Alan Fryer ⁶, Marie T Greally ⁷, Lisbeth Hoffmann ⁸, Nicolette S den Hollander ⁹, Marjolijn Jongmans ¹⁰, Sarina G Kant ⁹, Mary D King ¹¹, Sally A Lynch ⁷, Shane McKee ¹², Alina T Midro ¹³, Soo-Mi Park ¹⁴, Valeria Ricotti ¹¹, Enrico Tarantino ¹⁵, Marja Wessels ¹⁶, Maarit Peippo ¹⁷ and Anita Rauch ^1*

¹ Institute of Human Genetics, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
² Bioinformatics, Institute of Biochemistry, Friedrich-Alexander University Erlangen-Nuremberg, Erlang, Germany
³ Department of Clinical Genetics, Leiden University Medical Center, Leiden, Netherlands
⁴ Academic Department of Medical Genetics and Regional Genetic Services, St Mary's Hospital, Universit, United Kingdom
⁵ Kennedy Center, National Research Center for Genetics, Visual Impairment and Mental Retardation, Glo, Denmark
⁶ Department of Clinical Genetics, Royal Liverpool Children's Hospital, Liverpool, United Kingdom
⁷ National Centre for Medical Genetics, Our Lady's Hospital for Sick Children, Crumlin, Dublin, Republic of Ireland
⁸ Department of Pediatrics, Naestved Hospital, Naestved, Denmark
⁹ Department of Clinical Genetics, Leiden University Medical Centre, Leiden, Netherlands
¹⁰ Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands
¹¹ Department of Pediatric Neurology, Children's University Hospital, Temple Street, Dublin, Republic of Ireland
¹² Northern Ireland Regional Genetics Centre, Belfast City Hospital Trust, Belfast, United Kingdom
¹³ Department of Clinical Genetics, Medical University Bialystok, Bialystok, Poland
¹⁴ Department of Clinical Genetics, Addenbrooke's Hospital, Cambridge, United Kingdom
¹⁵ Section of Clinical Genetics, Department of Pediatrics, S. Chiara Hospital, Pisa, Italy
¹⁶ Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands
¹⁷ The Department of Medical Genetics, Väestöliitto, Helsinki, Finland

^* To whom correspondence should be addressed. E-mail: arauch{at}humgenet.uni-erlangen.de.

Accepted 27 June 2008

Abstract

Background: Haploinsufficiency of the gene encoding for transcription factor 4 (TCF4) was recently identified as the underlying cause of Pitt-Hopkins syndrome, a so far underdiagnosed mental retardation syndrome characterized by a distinct facial gestalt, breathing anomalies and severe mental retardation.

Methods and results: We performed TCF4 mutational analysis in 117 patients with Pitt-Hopkins syndrome like features and identified 16 novel mutations. All of these proven patients were severely mentally retarded and showed a distinct facial gestalt, 56% had breathing anomalies, 56% had microcephaly, 38% had seizures, and 44% had MRI anomalies.

Conclusion: We further delineate the mutational and clinical spectrum of Pitt-Hopkins syndrome and confirm its important role in the differential diagnosis of severe mental retardation.