PTCH1 duplication in a family with microcephaly and mild developmental delay

Abstract

With the exception of the X chromosome, genomic deletions appear to be more prevalent than duplications. Because of a lack of accurate diagnostic methods, submicroscopic duplications have been under-ascertained for a long period. The development of array CGH has enabled the detection of chromosomal microduplications with nearly the same sensitivity as deletions, leading to the discovery of previously unrecognized syndromes. Using a clinical targeted oligonucleotide array (CMA-V6.3 OLIGO), we identified an B360-kb duplication in 9q22.32 in a 21-month-old boy with developmental delay, failure to thrive, and microcephaly. The same duplication was identified in the patient's mother who is also microcephalic and mildly delayed. We have sequenced the chromosomal breakpoints and determined the duplication as tandem in orientation and 363 599 bp in size. The duplicated segment harbors the entire PTCH1 gene. Deletions or loss-of-function mutations of PTCH1 result in basal cell nevus syndrome (Gorlin syndrome), whereas gain-of-function mutations were proposed to lead to holoprosencephaly 7. We propose that patients with microcephaly or holoprosencephaly of unknown origin should also be screened for PTCH1 duplication.

DBS in the basolateral amygdala improves symptoms of autism and related self-injurious behavior: a case report and hypothesis on the pathogenesis of the disorder

“…Genetic studies/genome scans have revealed mutations in some patients with autism- associated symptoms. These genetic changes affect the transmission of both, GABA- and glutamatergic synapses (Hussman, 2001; Jamain et al, 2002; Derwińska et al, 2009, reviewed by Rubenstein and Merzenich, 2003; State, 2010). Reduced GABAergic signaling of interneurons of the L and BL nuclei might yield a “hyperexcitability-state” of the respective nuclei as found by Markram et al (2008) and reviewed by Markram and Markram (2010) in the rat-valproic acid-model of autism and in consequence impair both intraamygdaloid and amygdalo-cortical circuitry.…”

A wide methodological approach to identify a large duplication in CFTR gene in a CF patient uncharacterised by sequencing analysis

“…In addition to the comprehensive and quick characterisation of this new duplication, we have used array-CGH technology which provides both high-resolution and sensitivity to characterise copy-number variations [16,11]. The analysis showed a duplication of about 70 kb (proximally: last normal oligo 116,948,976 Mb, first duplicated one 116,963,849 Mb; distally: last duplicated oligo 117,030,994 Mb, first normal one 117,039,020 Mb) harbouring no less than 9 exons when considering the internal edges of the duplication (Fig.…”

Brief report adult patient presenting an interstitial (9) (q21.32q31.1) direct duplication resulting from the malsegregation of a paternal balanced insertional translocation

“…Previous reports showed that some patients with Fanconi anemia presented with pre‐ and postnatal growth retardation, microcephaly, and short stature (Giampietro et al, ; Joenje and Patel, ), suggesting that duplication of FANCC might contribute to the phenotypic features of the partial trisomy 9q syndrome. Derwińska et al () suggested that gain‐of‐function or duplication of PTCH1 was responsible for the microcephaly with or without holoprosencephaly. This is supported by our findings.…”

“…Rotthier et al () reported a SPTLC1 mutation in a French Gypsy patient with severe growth retardation, ID, and microcephaly. Derwińska et al () reported a 364‐kb duplication encompassing the entire PTCH1 gene in a mother and son with microcephaly and mild DD. Finally, patients with BICD2 mutations have not been described with a phenotype similar to the one observed in our patient.…”