Familial childhood onset, slowly progressive myopathy plus cardiomyopathy expands the phenotype related to variants in the TTN gene.

This report describes a novel TTN -related phenotype in two brothers, both affected by a childhood onset, very slowly progressive myopathy with cores, associated with dilated cardiomyopathy only in their late disease stages. Clinical exome sequencing documented in both siblings the heterozygous c.2089A>T and c.19426+2T>A variants in TTN. The c.2089A>T, classified in ClinVar as possibly pathogenic, introduces a premature stop codon in exon 14, whereas the c.19426+2T>A affects TTN alternative splicing. The unfeasibility of segregation studies prevented us from establishing the inheritance mode of the muscle disease in this family, although the lack of any reported muscle or heart symptoms in both parents might support an autosomal recessive transmission. In this view, the occurrence of cardiomyopathy in both probands might be related to the c.2089A>T truncating variant in exon 14, and the childhood onset, slowly progressive myopathy to the c.19426+2T>A splicing variant, possibly allowing translation of an almost full length TTN protein.

Estudio dínico y molecular en una familia con displasia cleidocraneal / Clinical and molecular study in a family with cleidocranial dysplasia

La displasia cleidocraneal es una displasia ósea infrecuente con patrón de herencia autosómico dominante, que se caracteriza por presentar talla baja, fontanelas amplias, hipoplasia mediofacial, ausencia o hipoplasia de clavículas y alteraciones orodentales. Es producida por mutaciones en el gen RUNX2 localizado en 6p21.1. Se presentan dos adolescentes masculinos (primos hermanos) con displasia cleidocraneal, los cuales mostraron mutación heterocigota, cambio de sentido (c.674G>A, p.R225Q) en el gen RUNX2, caracterizados por presentar fenotipo grave, como ausencia de clavículas, pero con variación en el retardo en el cierre de fontanelas, alteraciones dentales (anomalías en forma y número) y escoliosis, por lo que se demuestra la variación intrafamiliar en estos pacientes con el mismo genotipo.

Cleidocranial dysplasia is an uncommon bone dysplasia with an autosomal dominant inheritance pattern characterized by short stature, large fontanels, midface hypoplasia, absence or hypoplasia of clavicles and orodental alterations. This is produced by mutations in the RUNX2 gene located at 6p21.1. We report two male adolescents (cousins), with cleidocranial dysplasia who presented a heterozygous missense mutation (c.674G> A, p.R225Q) in the RUNX2 gene, characterized by severe phenotype, such as absent clavicles, but with variation in the delayed fontanel closure, dental abnormalities (anomalies in shape and number) and scoliosis, thus demonstrating intrafamilial variation in these patients with the same genotype.