We have just published our study on the relationship between deletions or truncating mutations at PTCHD1 and clinical features – the first such paper of its kind for PTCHD1- in the journal Clinical Genetics (Chaudhry et al [epub ahead of print]). This paper is available online, although it’s not currently open access: http://www.ncbi.nlm.nih.gov/pubmed/25131214; http://onlinelibrary.wiley.com/doi/10.1111/cge.12482/abstract.

In this study, through a large collaborative network  of researchers, we have identified 17 families with a PTCHD1 deletion, and report on the clinical features for 13 of these families. We also identified three families with truncating mutations within the PTCHD1 coding region. In these families there is either a single base-pair deletion or single base-pair insertion that disrupts the coding reading frame and leads to a premature STOP codon, thus prematurely truncating the translation from mRNA into protein. In addition to resulting in a shortened protein, such mutations typically trigger a mechanism known as nonsense-mediated mRNA decay (NMD), which targets the aberrant mRNA containing the premature STOP codon for degradation. This mechanism would deplete the PTCHD1 mRNA available for translation to protein.

In total, we studied 22 males and 1 female with PTCHD1 mutations. 40% of the subjects had autism spectrum disorder (ASD) or ASD-like behaviours. Global developmental delay was reported for 18 of the 23 (78%). Orofacial hypotonia was noted in 11 of the 23. Generalized hypotonia was found in six, and mild peripheral hypotonia in a further two.

There were very few significant medical co-morbidities. Eight reported mild problems with vision, including strabismus (three), jerky oculomotor movements (one), cataracts (one), astigmatism and myopia (one). One individual had mild hearing loss due to recurrent ear infections. Kyphosis was present in one family,  mild scoliosis in another. Pes planus with small joint hypermobility was present in one case. One individual had a diagnosis of celiac disease, and one had vesico-ureteral refulux and unilateral inguinal hernia, requiring surgical repair.

There was no easily distinguishable facial gestalt that would point to a PTCHD1 mutation diagnosis, however, subtle facial features were noted in some, in particular relating to the mid-facial hypotonia. Lip and mouth shape may also be relevant, but only subtly, and not in every case.

We hope that our study paves the way for a more detailed study, incorporating more PTCHD1 patients, and featuring a more detailed clinical and physical analysis. We also hope to conduct a similar analysis for subjects with either deletions just upstream of PTCHD1, as reported in Noor et al, 2010, also for subjects with missense variants within PTCHD1. However, for the latter, we need to find a method for assessing PTCHD1 function (and indeed some clear functionality!) so that the effects of missense changes may be evaluated empirically.

John B. Vincent, Ph.D.

Senior Scientist, MiND Lab at CAMH

Professor, University of Torono