Congenital general anosmia (CGA) is a neurological disorder entailing a complete innate inability to sense odors. While the mechanisms underlying vertebrate olfaction have been studied in detail, there are still gaps in our understanding of the molecular genetic basis of innate olfactory disorders. Applying whole-exome sequencing to a family multiply affected with CGA, we identified three members with a rare X-linked missense mutation in the TENM1 (teneurin 1) gene (ENST00000422452:c.C4829T). In Drosophila melanogaster, TENM1 functions in synaptic-partner-matching between axons of olfactory sensory neurons and target projection neurons and is involved in synapse organization in the olfactory system. We used CRISPR-Cas9 system to generate a Tenm1 disrupted mouse model. Tenm1(-/-) and point-mutated Tenm1(A) (/A) adult mice were shown to have an altered ability to locate a buried food pellet. Tenm1(A) (/A) mice also displayed an altered ability to sense aversive odors. Results of our study, that describes a new Tenm1 mouse, agree with the hypothesis that TENM1 has a role in olfaction. However, additional studies should be done in larger CGA cohorts, to provide statistical evidence that loss-of-function mutations in TENM1 can solely cause the disease in our and other CGA cases.

We performed whole exome or genome sequencing in eight multiply affected families with ostensibly isolated congenital anosmia. Hypothesis-free analyses based on the assumption of fully penetrant recessive/dominant/X-linked models obtained no strong single candidate variant in any of these families. In total, these eight families showed 548 rare segregating variants that were predicted to be damaging, in 510 genes. Three Kallmann syndrome genes (FGFR1, SEMA3A, and CHD7) were identified. We performed permutation-based analysis to test for overall enrichment of these 510 genes carrying these 548 variants with genes mutated in Kallmann syndrome and with a control set of genes mutated in hypogonadotrophic hypogonadism without anosmia. The variants were found to be enriched for Kallmann syndrome genes (3 observed vs. 0.398 expected, p = 0.007), but not for the second set of genes. Among these three variants, two have been already reported in genes related to syndromic anosmia (FGFR1 (p.(R250W)), CHD7 (p.(L2806V))) and one was novel (SEMA3A (p.(T717I))). To replicate these findings, we performed targeted sequencing of 16 genes involved in Kallmann syndrome and hypogonadotrophic hypogonadism in 29 additional families, mostly singletons. This yielded an additional 6 variants in 5 Kallmann syndrome genes (PROKR2, SEMA3A, CHD7, PROK2, ANOS1), two of them already reported to cause Kallmann syndrome. In all, our study suggests involvement of 6 syndromic Kallmann genes in isolated anosmia. Further, we report a yet unreported appearance of di-genic inheritance in a family with congenital isolated anosmia. These results are consistent with a complex molecular basis of congenital anosmia.

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Tracing the facial nerve trunk is an essential action in parotid surgery, because of the implications of injury to the nerve or its branches. More than a few landmarks that may help the surgeon in this task have been proposed (e.g., the posterior belly of the digastric muscle, the tragal pointer, among others), under the assumption that additional access methods improve the surgical technique and reduce the possibility of harmful post-operative consequences. Here we present evidence that the posterior auricular nerve may be used to trace the facial nerve trunk. We dissected 75 cadaveric heminecks, exposed the auricularis posterior muscle and adnexa, and attempted to follow the posterior auricular nerve to the facial nerve trunk. The auricularis posterior muscle, nerve, and artery were identified in all heminecks, securing an anatomically reliable route to the facial nerve trunk. Average length of the nerve from the auricularis posterior muscle to the facial nerve trunk was 28 mm (AE6.2 mm). The angle between the posterior auricular nerve and the vertical segment of the FN trunk was 39.5 (AE7.7 ). We conclude that the posterior auricular nerve may be used as a landmark to trace the facial nerve trunk. It is advantageous due to the relatively simple and consistent regional anatomy, and also because manipulation of this nerve does not present a risk given that the auricularis posterior muscle is vestigial. The proposed landmark is particularly important in revision surgery, where the pre-auricular anatomy may have been distorted and scarred by previous operations. Clin. Anat. 32:453-457, 2019.