Malgorzata J. M. Nowaczyk

Osteopathia striata with cranial sclerosis (OSCS) is an X-linked dominant condition characterised by metaphyseal striations, macrocephaly, cleft palate, and developmental delay in affected females. Males have a more severe phenotype with multi-organ malformations, and rarely survive. To date, only frameshift and nonsense variants in exon 2, the single coding exon of AMER1, or whole gene deletions have been reported to cause OSCS. In this study, we describe two families with phenotypic features typical of OSCS. Exome sequencing and multiplex ligation-dependent probe amplification (MLPA) did not identify pathogenic variants in AMER1. Therefore, genome sequencing was employed which identified two deletions containing the non-coding exon 1 of AMER1 in the families. These families highlight the importance of considering variants or deletions of upstream non-coding exons in conditions such as OSCS, noting that often such exons are not captured on probe or enrichment-based platforms because of their high G/C content.

During my third year of general pediatrics residency training, a patient well known to me and my fellow residents died unexpectedly. The child was an extremely bright and mature 8-year-old who had spent much of the last year of her life in our hospital being treated for cancer. Seemingly overnight, she became “too” sick (ICU sick, intubated and ventilated, on dialysis sick). She began to have intractable seizures, and with her family by her side, she died. The next morning, a colleague in his first year of residency asked how I was. I said that it had been a difficult week and I felt profoundly sad about the death of our patient. A look of relief came over his face. He told me that he was feeling despair. This was the first child he had cared for that had died. He had never felt such sadness before and felt guilty for feeling sad. He said that in medical school he had been told by a senior physician that it was the professional responsibility of a physician to “never feel more than 50% as sad as a patient’s family.” Faced with the reality of the death of a child, my colleague was left feeling confused, distressed, and disenfranchised from his own emotional response. “You put on the waterworks and it makes the parents feel better,” my genetics attending said. She seemed proud to have arrived at this simple remedy. She had just finished counseling a couple whose child had been diagnosed with a lethal genetic condition. Were the tears an act simulating empathy for … Address correspondence to Małgorzata Nowaczyk, MD, FRCPC, FCCMG, FACMG, Department of Pediatrics, McMaster Children’s Hospital, 1200 Main St W, Hamilton, ON L8N 3Z5, Canada. E-mail: nowaczyk{at}hhsc.ca

Aminoacyl‐tRNA synthetases (ARSs) are a group of ubiquitously expressed enzymes that are best known for their function in the first step of protein translation but have been increasingly associated with secondary functions including transcription and translation control and extracellular signaling. Mutations in numerous ARSs have been linked to a growing number of both autosomal dominant and autosomal recessive human diseases. The tyrosyl‐tRNA synthetase (YARS) links the amino acid tyrosine to its cognate tRNA. We report two siblings who presented with failure to thrive (FTT), hypertriglyceridemia, developmental delay, liver dysfunction, lung cysts, and abnormal subcortical white matter. Using exome sequencing the siblings were found to harbor bi‐allelic pathogenic‐appearing variants within the YARS gene (NM_003680.3):c.638C>T p.(Pro213Leu) and c.1573G>A p.(Gly525Arg). These YARS variants occur in the catalytic domain and the C‐terminal domain, respectively. Mutations in YARS have been previously associated with an autosomal dominant form of Charcot‐Marie‐Tooth (CMT); our findings suggest the disease spectrum associated with YARS dysregulation is broader than peripheral neuropathy.

Malsegregation of chromosomes during reproduction can result in uniparental disomy when associated with trisomy rescue, monosomy rescue or gamete complementation. Pathogenicity stemming from uniparental disomy in liveborns results from imprinting disorders or autozygosity for autosomal recessive disorders. We report on a girl with Prader–Willi syndrome and Tay–Sachs disease resulting from maternal uniparental disomy of chromosome 15. The child also had an isochromosome Xq. To further characterize the etiology of the aberrant chromosome 15 and the isochromosome Xq, SNP loci from both chromosomes were assessed in the proband and parents, and genome‐wide DNA methylation analysis was performed. SNP and DNA methylation analysis confirmed maternal uniparental heterodisomy around the Prader–Willi locus, while the region around the HEXA locus showed maternal uniparental isodisomy. This result is consistent with trisomy rescue of a maternal meiosis l error in a chromosome 15 with two meiotic recombinations. SNP analysis of the X chromosomes is consistent with a maternal origin for the isochromosome.

An call for papers on the topic of narrative medicine as it pertains to the practice of clinical genetics, this article briefly reviews the tenets of narrative medicine and the ethical issues associated with publishing patients' and doctors' stories. It is an invitation to the readership of the American Journal of Medical Genetics to share its stories of caring for and living with genetic conditions in our new column called Frameshifts.

Somatic and germline duplications of AKT3 and activating mutations of this gene have been reported in individuals with megalencephaly and hemimegalencephaly. We report on a patient with macrocephaly and a 3 Mb duplication on 1q43q44 that includes AKT3. This duplication was detected by array comparative genomic hybridization. The patient presented with moderate developmental delays in gross motor movements and speech. She also had macrocephaly, frontal bossing, hypertelorism, wide nasal bridge, small alae nares, short philtrum, prominent upper lip, and low‐set, protruding ears. The 3 Mb duplicated region contained 15 genes including AKT3. The observation of megalencephaly in a child with 1q43q44 duplication provides further evidence of involvement of AKT3 dosage imbalances in brain growth disturbance.