Four siblings of a consanguineous family presented at infancy with unique manifestations of Charcot-Marie-Tooth (CMT) disease. Profound cerebellar atrophy with ataxia and positive pyramidal signs were the presenting symptoms along with highly unique “fork and bracket” brainstem anomalies. Through whole exome sequencing, we identified a novel homozygous splice-site mutation within SBF1, encoding SET binding factor 1. Only four families with SBF1 mutations have been identified to date, all with CMT type 4B3. As the phenotype we describe is distinct from the classical disease delineation of CMT4B3, our data establish a new disease type with SBF1 mutations.

Androgen insensitivity syndrome (AIS) is caused by defects in the androgen receptor (AR) gene and is the most common aetiology of 46,XY disorders of sex development. Allelic variants in the AR gene are found in 90% of complete AIS (CAIS), but in only 28% to 50% of cases of partial AIS. Even a single nucleic acid change can disrupt splicing sites or splicing regulatory sequences, resulting in inadequate exon and intron recognition, ultimately leading to an aberrant transcript. Therefore, we tested the feasibility of conducting AR cDNA analysis from whole blood and from gonadal tissue in a patient with CAIS due to AR synonymous mutation (c.1530C > T, p.Ser510Ser; NM_000044.3), which led to an aberrant splicing site causing deletion of 92 nucleotides resulting in a very short transcript. AR cDNA sequencing was similar in the whole blood and in the gonadal tissue, with similar evidence of a consequent altered AR transcript. We propose that analysis of AR RNA extracted from whole blood with AR DNA sequencing can help to improve the frequency of molecular diagnosis, particularly for partial AIS.