ZDHHC15 as a candidate gene for autism spectrum disorder.

The phenotypic repercussion of ZDHHC15 haploinsufficiency is not well-known. This gene was initially suggested as a candidate for X-linked mental retardation, but such an association was later questioned. We studied a multiplex family with three members with autism spectrum disorder (ASD) by array CGH, karyotype, exome sequencing and X-chromosome inactivation patterns. Medical history interviews, cognitive and physical examinations, and sensory profiling were also assessed. The three family members with ASD (with normal cognitive abilities and an abnormal sensory profile) were the only carriers of a 1.7 Mb deletion in the long arm of chromosome X, involving: ZDHHC15, MAGEE2, PBDC1, MAGEE1, MIR384 and MIR325. The normal chromosome X was preferentially inactivated in female carriers, and the whole exome sequencing of an affected family member did not reveal any additional genetic variant that could explain the phenotype. Thus, in the present family, ASD segregates with a deletion on chromosome X that includes ZDHHC15. Considering our results together with gene data (regarding function, expression, conservation and animal/cellular models), ZDHHC15 is a candidate gene for ASD. Emerging evidence also suggests that this gene could be associated with other neurodevelopmental disorders, with incomplete penetrance and variable expressivity.

GLYT1 encephalopathy: Further delineation of disease phenotype and discussion of pathophysiological mechanisms.

GLYT1 encephalopathy is a form of glycine encephalopathy caused by disturbance of glycine transport. The phenotypic spectrum of the disease has not yet been completely described, as only four unrelated families with the disorder have been reported to date. Common features of affected patients include neonatal hypotonia, respiratory failure, encephalopathy, myoclonic jerks, dysmorphic features, and musculoeskeletal anomalies. All reported affected patients harbor biallelic genetic variants in SLC6A9. SNP array together with Sanger sequencing were performed in a newborn with arthrogryposis and severe neurological impairment. The novel genetic variant c.997delC in SLC6A9 was detected in homozygous state in the patient. At protein level, the predicted change is p.(Arg333Alafs*3), which most probably results in a loss of protein function. The variant cosegregated with the disease in the family. A subsequent pregnancy with ultrasound anomalies was also affected. The proband presented the core phenotypic features of GLYT1 encephalopathy, but also a burst suppression pattern on the electroencephalogram, a clinical feature not previously associated with the disorder. Our results suggest that the appearance of this pattern correlates with higher cerebrospinal fluid glycine levels and cerebrospinal fluid/plasma glycine ratios. A detailed discussion on the possible pathophysiological mechanisms of the disorder is also provided.

Epistasis for founder-specific inbreeding depression in rabbits.

Inbreeding depression is a topic of main interest in experimental and domestic species, although previous studies simplified this genetically complex effect to the linear (or quadratic) regression coefficient linked to the inbreeding coefficient of each individual or, in more recent studies, to founder-specific inbreeding coefficients. Going beyond generalizing to these traditional scenarios, our research focused on the analysis of gene-by-gene interactions leading to epistasis for inbreeding depression effects. Under a Bayesian context, inbreeding depression effects were evaluated for weaning weight (WW) in a commercial rabbit population founded from 4 bucks and 1 doe (MARET population). Founder-specific inbreeding depression effects for the 4 bucks ranged between -81.1 and 38.3 g for each 1% inbreeding. More interestingly, 2 epistatic interactions between the partial inbreeding coefficient of 2 bucks were also significant and negative, showing a -1.9 and -1.0 g reduction on WW. These results provide the first evidence of epistatic inbreeding depression phenomena in domestic species, emphasizing the complexity of the genetic architecture in mammals.

Crisis de atragantamiento en un lactante / Choking crises in an infant: type H tracheoesophagela fistula

Introducción. Las fístulas traqueoesofágicas (FTE) tipo H son malformaciones poco frecuentes que pueden asociarse a otras anomalías estructurales. Su diagnóstico puede retardarse debido a la inespecificidad de las manifestaciones clínicas. El tratamiento de elección es quirúrgico, a pesar de estar consiguiendo buenos resultados con técnicas de vaporización con laser. Observación clínica. Presentamos el caso de un lactante de un mes de vida con crisis de tos y cianosis coincidiendo con las tomas que se iniciaron en el nacimiento y se intensificaron progresivamente. Ante la sospecha de FTE se realiza un esofagograma dinámico que revela el paso de contraste de vía digestiva a tráquea por una pequeña fístula. Se confirma el diagnóstico de FTE tipo H por traqueobroncoscopia y se vaporiza con laser. Comentarios. Destacamos la importancia de la sospecha clínica en el diagnóstico de las FTE tipo H y su buen pronóstico con tratamiento quirúrgico(AU)

Introduction. Type H tracheoesophageal fistulas (TEF) are rare congenital malformations that may be associated to other structural anomalies. Their diagnosis may be delayed due to the non-specific clinical manifestations. Surgery is the mainstay of therapy, although recent data suggests that laser vaporization is a promising alternative. Clinical observation. We present the case of a one-month-old infant with repeat episodes of cough and cyanosis since birth. Given the high suspicion for a TEF a dynamic esophagogram was performed, which showed flow of contrast from the digestive tract to the trachea through a small fistula. The diagnosis of type H TEF was confirmed by tracheobronchoscopy, and the patient was successfully treated with laser vaporization. Comments. We highlight the importance of clinical suspicion in the diagnosis of type H TEF as well as their good outcome after laser vaporization(AU)