Population screening and cascade testing for carriers of SMA

Abstract

Spinal muscular atrophy (SMA) is one of the most common autosomal-recessive diseases, caused by absence of both copies of the survival motor neuron 1 (SMN1) gene. Identification of SMA carriers has important implications for individuals with a family history and the general population. SMA carriers are completely healthy and most are unaware of their carrier status until they have an affected child. A total of 422 individuals have been studied to identify SMA carriers. This cohort included 117 parents of children homozygously deleted for SMN1 (94% were carriers and 6% had two copies of SMN1; of these individuals, two in seven had the '2 þ 0' genotype, two in seven were normal but had children carrying a de novo deletion and three in seven were unresolved), 158 individuals with a significant family history of SMA (47% had one copy, 49% had two copies and 4% had three copies of SMN1) and 146 individuals with no family history of SMA (90% had two copies, 2% had one copy and 8% had three copies of SMN1). The SMA carrier frequency in the Australian population appears to be 1/49 and the frequency of two-copy SMN1 alleles and de novo deletion mutations are both at least 1.7%. A multimodal approach involving quantitative analysis, linkage analysis and genetic risk assessment (GRA), facilitates the resolution of SMA carrier status in individuals with a family history as well as individuals of the general population, providing couples with better choices in their family planning.

A mixed methods exploration of families’ experiences of the diagnosis of childhood spinal muscular atrophy

“…However, there is limited research around parental experiences of receiving a diagnosis of SMA. SMA is an autosomal recessive neuromuscular disease with a carrier frequency of 1 in 41 reported in the Australian population 5 and an estimated incidence of 1 in 6000 to 1 in 10 000 live births internationally. 6,7 Degeneration of motor neurons in the spine and lower brainstem lead to muscle weakness and atrophy.…”

Molecular characterization of SMN copy number derived from carrier screening and from core families with SMA in a Chinese population

“…1,[2][3][4] SMA is caused by the degeneration of anterior horn cells of the spinal cord, which leads to symmetric proximal muscle weakness and atrophy. 5 On the basis of the age at onset and the clinical course, SMA is classically subdivided into three types: type I is an infantile acute form, and shows the greatest severity; type II is an infantile chronic form with intermediate severity; and type III is a childhood and adolescent form and shows the mildest severity.…”

“…7 Mutations in the telomeric copy of the SMN gene (SMN1) are responsible for SMA, whereas SMN2 functions as a disease-modifying gene that can ameliorate the clinical severity of SMA in a copy-dependent manner. Each SMN gene encompasses 27 kb and comprises 9 exons (exons 1, 2a, 2b, and [3][4][5][6][7][8]. Typically, the DNA sequence of SMN1 differs from that of SMN2 by only five nucleotides: one in intron 6, one in exon 7, two in intron 7, and one in exon 8.…”

“…Using quantitative analysis of SMN1/SMN2 gene dosage, a range of molecular investigations of the incidence of carriers and the genetic burden of SMA in diverse ethnic populations have been carried out. 2,3,[13][14][15][16][17][18][19] However, a population-based study of SMA prevalence in mainland China has not yet been executed. Although some data have been reported for subjects from Taiwan and Hong Kong, the analyses included a relatively small number of SMA patients.…”

Pathogenesis of proximal autosomal recessive spinal muscular atrophy

“…In this review, we focus on the most common form, proximal autosomal recessive SMA, which is the second leading cause of neuromuscular disease (after muscular dystrophy) and the second most common autosomal recessive disease (after cystic fibrosis), with an incidence of at least 1 in 10,000 live births and a carrier frequency of 1 in 35 to 1 in 50 [25,78]. Since the initial description of SMA at the end of nineteenth century by Guido Werdnig, it has been postulated that pathological changes in SMA consist of four major features (the so-called "neuropathologic tetrad"): (1) loss of anterior horn cells (α-motoneurons as well as γ-motoneurons and interneurons), (2) empty cell beds (at locations of neuron loss), (3) glial cell bundles in the ventral spinal roots, and (4) heterotopic motoneurons (HMN) [85].…”