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Hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) is a rare autosomal recessive condition characterised by early-onset severe progressive neuropathy, variable degrees of ACC and cognitive impairment. Mutations in

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Hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) is a rare autosomal recessive condition characterised by early-onset severe progressive neuropathy, variable degrees of ACC and cognitive impairment. Mutations in SLC12A6 (solute carrier family 12, member 6) encoding the K+–Cl- transporter KCC3 have been identified as the genetic cause of HMSN/ACC. We describe fraternal twins with compound heterozygous mutations in SLC12A6 and much milder phenotype than usually described. Neither of our patients requires assistance to walk. The female twin is still running and has a normal intellect. Charcot-Marie-Tooth Examination Score 2 was 8/28 in the brother and 5/28 in the sister. Neurophysiology demonstrated a length-dependent sensorimotor neuropathy. MRI brain showed normal corpus callosum. Genetic analysis revealed compound heterozygous mutations in SLC12A6, including a whole gene deletion. These cases expand the clinical and genetic phenotype of this rare condition and highlight the importance of careful clinical phenotyping.

A term baby developed hypoventilation on day 1 of life requiring mechanical ventilation and had subsequent difficulty in weaning. Diagnostic workup for pulmonary, cardiac, metabolic, sepsis and structural CNS diseases were negative. In view of persistent hypoventilation despite raised pCO(2) levels in absence of any sedation, the diagnosis of Idiopathic. Congenital Central Hypoventilation Syndrome (CCHS) was considered. The baby was tested for Paired-like Homeobox 2B (PHOX2B) gene mutation and was found to have expanded alleles containing 10 polyalanine repeats producing genotype of 20/30 on chromosome 4p12 (The normal being 20/20). This is the first report of a neonate from India with genetically confirmed CCHS.

Pathogenic ELN gene mutations ( ELN , MIM#130160) cause AD Supravalvular Aortic Stenosis (SVAS) a congenital narrowing of the ascending aorta, and Cutis Laxa (CL) characterised by inelastic, loose-hanging skin. Variable phenotype and penetrance is apparent. Pathogenic ELN variants result in loss of function and include frameshift (most common), nonsense, splice site and missense variants. The well characterised contiguous gene deletion syndrome, Williams-Beuren syndrome includes SVAS and encompasses at least 114kb on 7q11.23 including the ELN gene; however, there are only 5 case reports of CNVs within ELN (single or multiple exons). Bristol Genetics Laboratory provides a UKGTN approved service for ELN gene sequencing (33 coding exons). In three years, 52 UK and foreign patients with SVAS, CL or features such as pulmonary artery stenosis and aortic dilation have been tested. 18/52 (34%) patients were heterozygous for a likely pathogenic variant including frameshift (6), nonsense (4), splice (4), and missense (4). 12 of these cases were novel variants, 5 are supported by segregation analysis and 1 is sporadic. The remaining novel variants are classed as possibly pathogenic as they are phenotypically compatible. 12/35 patients negative on sequencing have so far been screened for CNVs by MLPA (MRC Holland) covering the Williams-Beuren syndrome region, including 10 exons of the ELN gene (1, 3, 4, 6, 9, 16, 20, 26, 27 and 33) and in addition a bespoke MLPA assay including probes for exons 28 to 30, 32 and 3’UTR. 4/12 (33%) patients have a heterozygous deletion within the ELN gene. A mother and daughter with pulmonary stenosis and an extended family history have a deletion spanning exons 30 to 33. This deletion was also identified in another patient with SVAS and arteriopathy. A deletion of the 5’ end of the gene, involving at least exon 1 (but not exon 3) was identified in an infant with SVAS and pulmonary branch stenosis, and a deletion involving the entire coding region of the ELN gene and at least the first two exons of the adjacent 3’ gene LIMK1 was detected in a neonate who died at 2 months with SVAS, pulmonary stenosis and mild hypoplasia with PDA. The deletion was detected in this patient’s father who consequentially was found to have an aortic regurgitation and in a subsequent pregnancy of this family which was lost at 31 weeks with pulmonary stenosis and significant aortic stenosis MLPA analysis has enhanced the clinical utility of this service giving an increased diagnostic yield in patients with SVAS and CL and related presentations.

IGHMBP2 variants are associated with autosomal recessive distal spinal muscular atrophy 1 and distal hereditary motor neuronopathy type VI (dHMN6). Here we present two patients with potentially pathogenic variants in IGHMBP2 gene. Case 1-A 16 year old male patient with a progressive distal weakness and deformity of both hands and feet which presented in childhood. He also had marked pain (possibly radicular in origin) mainly in toes and chest, which was severe enough to require opiates. His hands showed marked thenar and hypothenar loss of muscle bulk. Neurophysiological investigations revealed an active and partial chronic denervation. Initial genetic investigations did not reveal any abnormalities. His DNA was subsequently analysed by gene panel testing. Gene panel testing (simultaneous testing of 56 genes associated with the common and the rare causes of different types of inherited peripheral neuropathy) revealed a single heterozygous frameshift variant in exon 5 of the IGHMBP2 gene; c.661del, p. (Thr221Profs*12). No second variant was identified in this patient. It is likely to be pathogenic as it is expected to cause premature truncation of the mRNA, leading either to the production of a non-functional protein, or no protein product from that allele due to nonsense mediated decay. Case 2 -A 12 year old female presented with gait problems, clumsiness, and recurrent falls at the age of 5 years. Neurophysiological investigations revealed a demyelinating neuropathy. Her initial gene testing was negative. Her DNA was subsequently analysed by gene panel testing. Two heterozygous frameshift variants were detected in the IGHMBP2 gene; c.2356delG, p. (Ala786Profs*45) in exon 13, and c.2911_2912delAG, p. (Arg971Glufs*4) in exon 15. Parents of the proband were tested and each was found to be heterozygous for one IGHMBP2 variant, confirming that the two variants are in trans in their daughter. Further studies will be needed to establish pathogenicity.

Background Inherited peripheral neuropathy (IPN) is a clinically and genetically heterogeneous group of disorders with more than 90 genes associated with the different subtypes. Sequential gene screening is gradually being replaced by next generation sequencing (NGS) applications. Methods We designed and validated a targeted NGS panel assay including 56 genes associated with known causes of IPN. We report our findings following NGS panel testing of 448 patients with different types of clinically-suspected IPN. Results Genetic diagnosis was achieved in 137 patients (31 %) and involved 195 pathogenic variants in 31 genes. 93 patients had pathogenic variants in genes where a resulting phenotype follows dominant inheritance, 32 in genes where this would follow recessive inheritance, and 12 presented with X-linked disease. Almost half of the diagnosed patients (64) had a pathogenic variant either in genes not previously available for routine diagnostic testing in a UK laboratory (50 patients) or in genes whose primary clinical association was not IPN (14). Seven patients had a pathogenic variant in a gene not hitherto indicated from their phenotype and three patients had more than one pathogenic variant, explaining their complex phenotype and providing information essential for accurate prediction of recurrence risks. Conclusions Our results demonstrate that targeted gene panel testing is an unbiased approach which overcomes the limitations imposed by limited existing knowledge for rare genes, reveals high heterogeneity, and provides high diagnostic yield. It is therefore a highly efficient and cost effective tool for achieving a genetic diagnosis for IPN. Electronic supplementary material The online version of this article (doi:10.1186/s12881-015-0224-8) contains supplementary material, which is available to authorized users.