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Table of Contents    
Year : 2018  |  Volume : 66  |  Issue : 4  |  Page : 1162-1165

Identification of a novel SLC12A6 pathogenic variant associated with hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) in a non-French-Canadian family

1 Laboratorio de Biología Molecular, Departamento de Genética Humana, Coyoacán, Ciudad de México, México
2 Servicio de Neurofisiología, Instituto Nacional de Pediatría, Coyoacán, Ciudad de México, México

Date of Web Publication18-Jul-2018

Correspondence Address:
Dr. Miguel A Alcántara-Ortigoza
Laboratorio de Biología Molecular, Departamento de Genética Humana, Instituto Nacional de Pediatría, Secretaría de Salud, Avenida Insurgentes Sur 3700-C, Insurgentes Cuicuilco, Coyoacán, C.P. 04530, Ciudad de México
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.236987

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How to cite this article:
Rius R, González-del Angel A, Velázquez-Aragón JA, Cordero-Guzmán LM, Muñoz-Hernández SE, Alcántara-Ortigoza MA. Identification of a novel SLC12A6 pathogenic variant associated with hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) in a non-French-Canadian family. Neurol India 2018;66:1162-5

How to cite this URL:
Rius R, González-del Angel A, Velázquez-Aragón JA, Cordero-Guzmán LM, Muñoz-Hernández SE, Alcántara-Ortigoza MA. Identification of a novel SLC12A6 pathogenic variant associated with hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) in a non-French-Canadian family. Neurol India [serial online] 2018 [cited 2020 Jul 12];66:1162-5. Available from:


Hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC, MIM#218000), or Andermann syndrome, is an autosomal recessive disease characterized by a progressive sensory-motor polyneuropathy with partial or complete ACC and is conditioned by biallelic pathogenic variants in the SLC12A6 gene (15q14, MIM*604878), which encodes two main isoforms (KCC3a and KCC3b) of a potassium-chloride co-transporter implicated in axon volume control and migration, neuronal development, and peripheral nervous system integrity.[1],[2],[3] Most of HMSN/ACC patients come from the French-Canadian (FC) population due to a founder effect, where 99% of them are homozygous for the SLC12A6 pathogenic variant, c. 2436del or p.(Thr813Profs*2).[3] The global incidence of this disease is not known, and only 16 affected families outside of the FC population have been molecularly confirmed to date [Supplementary table 1].[1],[3],[4],[5],[6],[7],[8],[9],[10] This rare condition has not previously been reported in the Mexican population.

An 8-year old male and his 9-year old sister, born to healthy nonconsanguineous parents from Mexico City, were referred due to intellectual disability and hypotonia that began in the first year of life. The female patient could not complete complex sentences or differentiate letters from numbers, and she had never been independent in performing daily activities. In contrast, by age 6, the male patient could name colors, identify body parts, eat by himself, and formulate complex sentences. Both experienced progressive weakness and muscular atrophy, leading to severe impairments in motor skills, limiting their unassisted walking and daily activities. In addition to intellectual disability, both affected siblings exhibited an absence of deep tendon reflexes as well as agenesis (affected sister) or hypoplasia (affected brother) of the corpus callosum (CC) [Figure 1], and sensory-motor polyneuropathy. These findings were consistent with the diagnosis of HMSN/ACC [Table 1] and [Table 2]. Clinical examinations of both parents were normal.
Figure 1: Left: Brain magnetic resonance imaging showing hypoplasia of the corpus callosum in the male patient (a) and complete agenesis of the corpus callosum in the female patient (b). Right: Partial electropherograms of exon 16 of SLC12A6 in members of a Mexican HMSN/ACC family, showing the wild-type sequence in the father and heterozygous NM_133647.1:c.2097dup or p.(Trp700Leufs*19) genotypes (arrows) in both affected siblings and their mother

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Table 1: Clinical, electrophysiological, and MRI findings in the Mexican affected siblings compared with those reported in French-Canadians with HMSN/ACC[a]

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Table 2: Nerve conduction studies

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To confirm the diagnosis of HMSN/ACC, we isolated leukocyte-derived genomic deoxyribonucleic acid (DNA) from both affected siblings and their parents and used polymerase chain reaction (PCR) to amplify the 25 exons and the exon-intron borders of the SLC12A6 gene (NG_007951.1, NM_133647.1), including the alternative first exon of the KCC3b isoform (NM_005135.2). The automated complete Sanger s equencing of the SLC12A6 amplicons revealed the presence of a novel heterozygous frameshift variant, c.2097dup or p.(Trp700Leufs*19), in exon 16 of both patients and their carrier mother [Figure 1]. We further noted that both siblings carried identical heterozygous genotypes for the rs2290940 (exon 9), rs17236798 (exon 11), and rs4577050 (exon 22) polymorphisms; for the latter, an observed homozygous C/C maternal genotype along with a heterozygous C/T paternal genotype allowed us to establish that both heterozygous C/T siblings inherited the same T paternal SLC12A6 allele. However, we were unable to identify the paternal mutated allele by Sanger sequencing. In an effort to identify this allele, we isolated leukocyte-derived messenger ribonucleic acid (mRNA) from the father and both patients, generated six overlapping cDNA fragments covering the entire coding sequence of the major SLC12A6 isoform (KCC3a, NM_133647.1) and performed reverse transcriptase-PCR followed by direct sequencing. Furthermore, to exclude multiexonic or whole-gene deletions/duplications, we conducted a quantitative real-time PCR (qPCR) assay of coding exons 8, 13, 22, and 25 of the KCC3a isoform in the male patient. Despite these efforts, we failed to identify the paternally derived pathogenic allele.

Here, we present the first Mexican patients with HMSN/ACC. These kindred siblings represent the 17th reported non-FC HMSN/ACC family [Supplementary Table 1]. Previous descriptions have noted intra-familial variability in HMSN/ACC either for generalized seizures [5] or for the CC structural abnormalities.[6] Although it is known that epileptiform discharges could contribute to a more pronounced cognitive deterioration,[7],[11] this finding was only seen in our male patient with less neurological involvement [Table 1], indicating that such discharges could not account for the differences in the neurodevelopmental performances in both siblings. Also, intra-familial variability for CC abnormalities was observed, with the female patient exhibiting complete ACC while the male patient presented with hypoplasia of the CC [Figure 1] and milder intellectual disability. However, without the identification of the second pathogenic allele, it is difficult to establish further phenotype–genotype correlations. The Slc12a6-/- mice model develops hypoplasia but not complete ACC;[2] instead in humans, there is no clear correlation between the SLC12A6 genotype and the resulting CC phenotype. For instance, in a German family where the affected siblings had an identical compound heterozygous genotype, only the male member presented with ACC.[6] Moreover, patients with the recently described homozygous c.745+2T>A variant, predicted to cause loss-of-function effect, presented with different phenotypes—with a normal brain magnetic resonance imaging in the Arab proband [9] in contrast with the presence of ACC in both affected siblings of Pakistani origin.[10] These suggest that other still unknown genes and/or environmental factors may modify the phenotypic spectrum of the CC in HMSN/ACC.[1]

All of the patients reported to date have biallelic pathogenic variants in the SLC12A6 gene, either in the homozygous state (i.e., FC patients) or in a compound heterozygous state (i.e., the German patients). However, given that these findings include only 16 non-FC families [Supplementary Table 1], we consider that the worldwide mutational spectrum of SLC12A6 is still largely unknown. The novel frameshift variant identified herein is the first to be described in exon 16, and the first to reside in the 12th transmembrane KCC3 domain. It resembles most of the pathogenic alleles described to date for HMSN/ACC in both FC and non-FC patients,[3],[5],[8],[12] in that, it removes most of the C-terminal portion of the protein, which appears to be required for its stability and localization to the cytoplasmic membrane.[2] However, despite having performed complete sequencing, cDNA analysis, and gene-dosage analysis for SLC12A6, we failed to identify the paternally derived pathogenic variant in both affected siblings and were thus unable to molecularly confirm a strict diagnosis of HMSN/ACC. Several possibilities could explain this finding. First, due to the rarity of HMSN/ACC, it is difficult to determine the proportion of non-FC patients who might require additional assessments beyond SLC12A6 Sanger sequencing. There are other well-studied autosomal recessive conditions in which sequencing of the causative gene fails to identify the responsible genotype in all affected patients. In cystic fibrosis, for example, it has been estimated that both pathogenic variants can be identified through a complete cystic fibrosis transmembrane conductance regulator (CFTR) gene sequencing analysis in only 63% of US non-white individuals.[13] Thus, sequencing may not identify the second (or even both) pathogenic allele(s) in 100% of non-FC HMSN/ACC patients. Second, there are six known SLCA12A6 isoforms (, and they exhibit distinct tissue-specific expression patterns.[2] So, in our patients, the paternally derived and mutated isoform might not be expressed in the analyzed peripheral blood leukocytes. Third, there could be a larger genomic rearrangement that was not identified by our cDNA and qPCR analyses, although to our knowledge, no SLC12A6 gene inversion, whole-exon deletion or duplication has been reported in any HMSN/ACC patient, and currently, no multiplex ligation-dependent probe amplification (MLPA) assay for SLC12A6 is commercially available. Thus, high-density chromosomal microarray analysis and/or next-generation sequencing could be considered as means to document the paternally derived pathogenic variant; these techniques are still not available as part of a routine diagnostic approach in many countries such as ours.

Although, the carrier status documented in the mother might be coincidental, this would seem unlikely, since the c. 2097dup SLC12A6 allele has not been described in any studied populations at Exome Variant Server, Genome Aggregation Database, dbSNP, and 1000 Genomes Browser Database. Furthermore, this pathogenic variant co-segregates with the HMSN/ACC trait in both siblings, which also share the same SLC12A6 paternal allele, as noted by the rs4577050 genotypes.

Finally, most of the reports lack any detailed description of nerve conduction studies. Lourenco et al., (2012) described a Brazilian homozygous c. 571_572dup or p.(Tyr192Serfs*12) patient who presented with nonuniform nerve conduction [Supplementary Table 1].[8] Interestingly, the nerve conduction studies performed on the present cases revealed a similar pattern [Table 2]. Although this has not been described in other cases, we should not assume an absence of this electrophysiological feature, so we consider that more nerve conduction data are needed to elucidate whether or not the nonuniform nerve conduction is a distinctive trait of the disease.

In closing, based on the present and previous reports, we suggest that HMSN/ACC should be included in the differential diagnosis of hereditary neuropathy in non-FC populations. Given that the full mutational spectrum of the disease is currently unknown, additional techniques must be defined if we hope to characterize the SLC12A6 genotypes of non-FC HMSN/ACC patients in whom complete Sanger sequencing is insufficient, as seen in the present cases.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support, sponsorship and acknowledgments

Programa E022 Investigación y Desarrollo Tecnológico en Salud. Instituto Nacional de Pediatría, Ciudad de México, MÉXICO. RR expresses gratitude to the Carlos Slim Foundation for granting a scholarship. We thank Drs. Moisés Fiesco and Marisol González for their participation in the initial medical assessment.

Conflicts of interest

There are no conflicts of interest.

  References Top

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