Autosomal recessive distal hereditary motor neuronopathy-7 (HMNR7) is characterized by onset of lower leg weakness in the first decade. Affected individuals have difficulty climbing stairs and problems standing on their heels. Most patients have foot deformities, and some may have leg muscle atrophy. The disorder is slowly progressive and often involves the upper limbs¹.

Prevalence

Biallelic variants found in 0.01% of 100 KGP participants; enriched in those with motor disease. 80% of VWA1 pathogenic variants are expansions/contractions². The repeat expansion was found in several ethnicities; founder mutation 7,000 years ago³.

Age of Onset

Typical: 1-3³; Range: 0-10¹.

HPO Terms

HP:0001252 Hypotonia HP:0001265 Hyporeflexia HP:0001308 Tongue fasciculations HP:0001371 Flexion contracture HP:0001761 Pes cavus HP:0001762 Talipes equinovarus HP:0002359 Frequent falls HP:0003326 Myalgia HP:0003401 Paresthesia HP:0003458 EMG: myopathic abnormalities HP:0003691 Scapular winging HP:0007002 Motor axonal neuropathy HP:0007210 Lower limb amyotrophy HP:0008959 Distal upper limb muscle weakness HP:0008994 Proximal lower limb muscle weakness HP:0008997 Proximal upper limb muscle weakness HP:0009027 Foot dorsiflexor weakness HP:0009053 Distal lower limb muscle weakness HP:0010830 Impaired tactile sensation

Association

Mendelian

Locus

hg19chr1:1371178-1371198

hg38chr1:1435798-1435818

t2tchr1:870158-870178

Details

The reference allele contains 2 copies of the 10 bp motif. The 3 copy allele is the most common pathogenic allele when homozygous or in trans with another pathogenic VWA1 variant. The 1 copy allele also causes a frameshift and has been proposed as likely pathogenic. Pathogenicity depends on reading frame rather than repeat size, so a simple pathogenic range does not apply for this locus^3,2.

Mechanism

LoF

Loss of function⁴.

Detection

Year

2021³

Location in Gene

Coding Exon 1

Gene Strand

Alleles

Ref. Motif

GGCGCGGAGC

Ranges

Benign (ref.)

–

Benign (gene)

–

Pathogenic (ref.)

AGCGGCGCGG

Pathogen. (gene)

AGCGGCGCGG

Unknown (ref.)

–

Unknown (gene)

–

Interruption (ref.)

–

Interrup. (gene)

–

gnomAD

References

Direct supporting references for info on this page.

1omim:619216

Resources for Genetics Professionals — Genetic Disorders Caused by Nucleotide Repeat Expansions and Contractions

Stephanie E.,Wallace, Lora JH,Bean

GeneReviews® [Internet] · 2022-10-20

genereviews:NBK535148

An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy.

Alistair T,Pagnamenta, Rauan,Kaiyrzhanov, Yaqun,Zou, Sahar I,Da'as, Reza,Maroofian, Sandra,Donkervoort, Natalia,Dominik, Marlen,Lauffer, Matteo P,Ferla, Andrea,Orioli, Adam,Giess, Arianna,Tucci, Christian,Beetz, Maryam,Sedghi, Behnaz,Ansari, Rita,Barresi, Keivan,Basiri, Andrea,Cortese, Greg,Elgar, Miguel A,Fernandez-Garcia, Janice,Yip, A Reghan,Foley, Nicholas,Gutowski, Heinz,Jungbluth, Saskia,Lassche, Tim,Lavin, Carlo,Marcelis, Peter,Marks, Chiara,Marini-Bettolo, Livija,Medne, Ali-Reza,Moslemi, Anna,Sarkozy, Mary M,Reilly, Francesco,Muntoni, Francisca,Millan, Colleen C,Muraresku, Anna C,Need, Andrea H,Nemeth, Sarah B,Neuhaus, Fiona,Norwood, Marie,O'Donnell, Mary,O'Driscoll, Julia,Rankin, Sabrina W,Yum, Zarazuela,Zolkipli-Cunningham, Isabell,Brusius, Gilbert,Wunderlich, Mert,Karakaya, Brunhilde,Wirth, Khalid A,Fakhro, Homa,Tajsharghi, Carsten G,Bönnemann, Jenny C,Taylor, Henry,Houlden

Brain : a journal of neurology · 2021-03-03

pmid:33559681

Sequence composition changes in short tandem repeats: heterogeneity, detection, mechanisms and clinical implications.

Indhu-Shree,Rajan-Babu, Egor,Dolzhenko, Michael A,Eberle, Jan M,Friedman

Nature reviews. Genetics · 2024-03-11

pmid:38467784