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Abstract Background Hearing loss is a common inborn neurosensory condition. Hearing loss is very heterogeneous, and while screening programs exist for children, adolescents and adults with late-onset hearing loss often do not get referrals to geneticists. Objective To diagnose the cause of hearing impairment in two related late-onset hearing loss patients—father and son—on a molecular level. Both underwent audiological examinations, and both had moderate hearing loss. Case presentation. We used massive parallel sequencing, Sanger sequencing, MLPA, and standard audiological methods. We identified an inherited autosomal dominant likely causative variant in the TBC1D24 gene of both patients. They did not show any other TBC1D24 spectrum-related symptoms. Furthermore, the younger patient was found to be compound heterozygous for two variants in STRC gene. Conclusions Only a few dozen TBC1D24 hearing loss patients have been reported. On the contrary, STRC is a common hearing loss cause. We speculate that in the younger patient, the phenotype is caused by a combination of effects of both genes. The older patient’s phenotype is more likely caused only by the TBC1D24 variant. We believe that more attention should be paid to adolescent and adult-onset hearing loss patients, and more frequent referrals to geneticists are warranted.

Folate deficiency in the critical developmental period has been repeatedly associated with an increased risk of Autism spectrum disorders (ASD), but the key pathophysiological mechanism has not yet been identified. In this work, we focused on identifying genes whose defect has similar consequences to folate depletion in the metabolic network. Within the Flux Balance Analysis (FBA) framework, we developed a method of blocked metabolites that allowed us to define the metabolic consequences of various gene defects and folate depletion. We identified six genes (GART, PFAS, PPAT, PAICS, ATIC, and ADSL) whose blocking results in nearly the same effect in the metabolic network as folate depletion. All of these genes form the purine biosynthetic pathway. We found that, just like folate depletion, the blockade of any of the six genes mentioned above results in a blockage of purine metabolism. We hypothesize that this can lead to decreased adenosine triphosphate (ATP) and subsequently, an S-adenosyl methionine (SAM) pool in neurons in the case of rapid cell division. Based on our results, we consider the methylation defect to be a potential cause of ASD, due to the depletion of purine, and consequently S-adenosyl methionine (SAM), biosynthesis.

Abstract Background With only 11 patients reported, 5p tetrasomy belongs to rare postnatal findings. Most cases are due to small supernumerary marker chromosomes (sSMCs) or isochromosomes. The patients share common but unspecific symptoms such as developmental delay, seizures, ventriculomegaly, hypotonia, and fifth finger clinodactyly. Simple interstitial duplications leading to trisomies of parts of 5p are much more frequent and better described. Duplications encompassing 5p13.2 cause a defined syndrome with macrocephaly, distinct facial phenotype, heart defects, talipes equinovarus, feeding difficulties, respiratory distress and anomalies of the central nervous system, developmental delay and hypotonia. Case presentation We present a boy with dysmorphic features, developmental delay, intellectual disability and congenital anomalies, and a mosaic sSMC inv dup(5)(p15.33p15.1). He is the fourth and the oldest reported patient with distal 5p tetrasomy. His level of mosaicism was significantly different in lymphocytes (13.2%) and buccal cells (64.7%). The amplification in our patient is smaller than that in the three previously published patients but the only phenotype difference is the absence of seizures in our patient. Conclusions Our observations indicate that for the assessment of prognosis, especially with respect to intellectual functioning, the level of mosaicism could be more important than the extent of amplification and the number of extra copies. Evaluation of the phenotypical effect of rare chromosomal aberrations is challenging and each additional case is valuable for refinement of the genotype-phenotype correlation. Moreover, our patient demonstrates that if the phenotype is severe and if the level of sSMC mosaicism is low in lymphocytes, other tissues should be tested.