Tip of the iceberg: a tertiary care centre retrospective study of left ventricular hypertrophy aetiologies.

AIMS: To phenotype patients referred to a tertiary centre for the exploration of a left ventricular hypertrophy (LVH) starting from 12 mm of left ventricular wall thickness (LVWT). METHODS AND RESULTS: Consecutive patients referred for aetiological workup of LVH, beginning at 12 mm of LVWT were retrospectively included in this tertiary single-centred observational study. Patients presenting with severe aortic stenosis were excluded. Aetiological workup was reviewed for each subject and aetiologies were adjudicated by expert consensus.Among 591 patients referred for LVH aetiological workup, 41% had a maximal LVWT below 15 mm. LVH aetiologies were led by cardiac amyloidosis (CA, 34.3%), followed by sarcomeric hypertrophic cardiomyopathy (S-HCM, 32.1%), hypertensive cardiomyopathy (21.7%), unknown aetiology (7.6%) and other (4.2%), including Anderson-Fabry's disease (1.7%). CA and S-HCM affected over 50% of patients with mild LVH (12-14 mm); the prevalence of these aetiologies rose with LVH severity. Among patients with Anderson-Fabry's disease, 4 (40%) had a maximal LVWT <15 mm. CONCLUSIONS: Mild LVH (ie, 12-14 mm) conceals multiple aetiologies that can lead to specific treatment, cascade family screening and specific follow-up. Overall, CA is nowadays the leading cause of LVH in tertiary centers.

The expanding spectrum of COL2A1 gene variants IN 136 patients with a skeletal dysplasia phenotype.

Heterozygous COL2A1 variants cause a wide spectrum of skeletal dysplasia termed type II collagenopathies. We assessed the impact of this gene in our French series. A decision tree was applied to select 136 probands (71 Stickler cases, 21 Spondyloepiphyseal dysplasia congenita cases, 11 Kniest dysplasia cases, and 34 other dysplasia cases) before molecular diagnosis by Sanger sequencing. We identified 66 different variants among the 71 positive patients. Among those patients, 18 belonged to multiplex families and 53 were sporadic. Most variants (38/44, 86%) were located in the triple helical domain of the collagen chain and glycine substitutions were mainly observed in severe phenotypes, whereas arginine to cysteine changes were more often encountered in moderate phenotypes. This series of skeletal dysplasia is one of the largest reported so far, adding 44 novel variants (15%) to published data. We have confirmed that about half of our Stickler patients (46%) carried a COL2A1 variant, and that the molecular spectrum was different across the phenotypes. To further address the question of genotype-phenotype correlation, we plan to screen our patients for other candidate genes using a targeted next-generation sequencing approach.

Loss-of-function mutations in SOX10 cause Kallmann syndrome with deafness.

Transcription factor SOX10 plays a role in the maintenance of progenitor cell multipotency, lineage specification, and cell differentiation and is a major actor in the development of the neural crest. It has been implicated in Waardenburg syndrome (WS), a rare disorder characterized by the association between pigmentation abnormalities and deafness, but SOX10 mutations cause a variable phenotype that spreads over the initial limits of the syndrome definition. On the basis of recent findings of olfactory-bulb agenesis in WS individuals, we suspected SOX10 was also involved in Kallmann syndrome (KS). KS is defined by the association between anosmia and hypogonadotropic hypogonadism due to incomplete migration of neuroendocrine gonadotropin-releasing hormone (GnRH) cells along the olfactory, vomeronasal, and terminal nerves. Mutations in any of the nine genes identified to date account for only 30% of the KS cases. KS can be either isolated or associated with a variety of other symptoms, including deafness. This study reports SOX10 loss-of-function mutations in approximately one-third of KS individuals with deafness, indicating a substantial involvement in this clinical condition. Study of SOX10-null mutant mice revealed a developmental role of SOX10 in a subpopulation of glial cells called olfactory ensheathing cells. These mice indeed showed an almost complete absence of these cells along the olfactory nerve pathway, as well as defasciculation and misrouting of the nerve fibers, impaired migration of GnRH cells, and disorganization of the olfactory nerve layer of the olfactory bulbs.