Evaluation of the SMN and NAIP genes in a family: homozygous deletion of the SMN2 gene in the fetus and outcome of the pregnancy.

Spinal muscular atrophy (SMA) is characterized by the death of motor neurons that leads to diffuse proximal and distal weakness, hypotonia, and muscular atrophy. Survival motor neuron (SMN), neuronal apoptosis inhibitory protein (NAIP), and GTF2H2 genes were shown to be associated with SMA. SMN protein is encoded by two genes that are two almost identical copies, telomeric SMN (SMN1) and centromeric SMN (SMN2). The SMN1 gene is homozygously absent in approximately 95% of SMA patients, whereas loss of SMN2 has been reported not to cause SMA. Prenatal diagnosis is widely applied for those pregnancies at risk for SMA, and here we present a family in which each of the parents is carrying SMN1 and NAIP gene deletions in one allele and SMN2 deletion in the other. Their first child was carrying SMN1 and NAIP gene deletions in both alleles and died at the age of 9 months. During the second pregnancy, the fetus was found to carry SMN2 deletion in both alleles, and the pregnancy was not terminated. The family was referred to our genetics department because of a risk of spinal muscular atrophy (SMA) in the fetus. The previous child of the family was found to have SMA and died at the age of 9 months. He was noted to have generalized weakness and severe hypotonia, absent stretched reflexes, and fasciculation in the tongue at the age of 4 months. The serum creatine kinase level was 28 IU. The electromyelography showed denervation of the muscles, paucity of movement, and fasciculation. The muscle biopsy revealed degeneration of muscle fibers without inflammation, fibrosis, or histochemical abnormality. Restriction fragment length polymorphism (RFLP) method was used for detecting the deletion within the survival motor neuron (SMN) gene. For exon 7 deletion and exon 8 deletion, restriction enzymes DraI and DdeI were used, respectively. DNA analysis revealed exon 7 and exon 8 deletions of the SMN gene and exon 6 of the NAIP gene on both chromosomes 5. The parents were considered to carry centromeric SMN (cenSMN–SMN2) deletion in one allele, and telomeric SMN (telSMN–SMN1) and NAIP gene deletions in the other allele. During the second pregnancy, chorionic villus sampling was performed at 11 weeks of gestation, and DNA was extracted to screen for SMA-causing mutations. The results showed deletions of exons 7 and 8 of the SMN2 gene on both chromosomes 5, while no deletion was detected in the SMN1 gene. The pregnancy was not terminated according to the mutation analysis, and the mother gave birth to a healthy male child. Clinical assessments during the growing-up period and the physical examination of the child at the age of 4 years were normal. Homozygous deletion of the SMN2 gene is presented in this report. SMA is caused by mutations in the telomeric SMN1 gene. Deletions in exons 7 and 8 of the telomeric copy occur in more than 90% of patients regardless of the disease severity (Lefebvre et al., 1995). It has been suggested that SMN2 copy number modulates the severity of the disease (MacLeod et al., 1999). Homozygous deletion of exons 7 and 8 of the SMN2 is present in approximately 5% of the normal population (Talbot et al., 1997). NAIP has also been reported to have a modifying effect on the phenotype (DerakhshandehPeykar et al., 2007). It was found to be homozygously deleted in 1.8% of SMA carriers and 67% of SMA type I patients (Erdem et al., 1999). The availability of prenatal diagnosis for families at risk for SMA is important, and many studies regarding the frequency of SMA, the SMA-related gene pool, and the prenatal prediction of SMA in Turkish population have been conducted (Erdem et al., 1999; Savas et al., 2000, 2002). The deletion frequencies of SMN exons 7 and 8, NAIP, and GTF2H2 in SMA type I patients are found to be 93%, 67%, and 16%, respectively (Erdem et al., 1999). In the presented family, the presence of SMN1 and NAIP gene deletions in the first child combined with the absence of SMN2 in the fetus is a result of the parents’ carrier status for SMA. It was considered that