Abstract：
Background: Hereditary sensory and autonomic neuropathies (HSANs) are rare heterogeneous group of neurological disorders caused by peripheral nerve deterioration. The HSANs sub-clinical classes have clinical and genetic overlap which often lead to misdiagnosis. In the present study a Pakistani family with five affected members suffering from severe neuropathy were genetically analyzed to identify the disease causative element in the family.
Methods: Genome wide high-density single nucleotide polymorphism (SNP) microarray analysis was carried out followed by whole exome sequencing of the affected proband and another affected sibling. Shared homozygous regions in all severely affected members were identified through homozygosity mapping approach.
Results: The largest homozygous region of 14.1 Mb shared by the five severely affected members of the family was identified on chromosome 2. Subsequent exome sequencing identified a novel single nucleotide deletion c.2658del; p.(Ser887Profs*64) in KIF1A. Segregation analysis revealed that this mutation was homozygous in all five affected individuals of the family with severe clinical manifestation, while members of the family that were heterozygous carriers shared abnormal skin features (scaly skin) only with the homozygous affected members.
Conclusions: A novel frameshift mutation p.(Ser887Profs*64) in KIF1A is the potential cause of severe HSANIIC in a Pakistani family along with incomplete penetrance in mutation carriers. We demonstrate that using a combination of different techniques not only strengthens the gene finding approach but also helps in proper sub-clinical characterization along with identification of mutated alleles exhibiting incomplete penetrance leading to intrafamilial clinical variability in HSAN group of inherited diseases.
Methods: Genome wide high-density single nucleotide polymorphism (SNP) microarray analysis was carried out followed by whole exome sequencing of the affected proband and another affected sibling. Shared homozygous regions in all severely affected members were identified through homozygosity mapping approach.
Results: The largest homozygous region of 14.1 Mb shared by the five severely affected members of the family was identified on chromosome 2. Subsequent exome sequencing identified a novel single nucleotide deletion c.2658del; p.(Ser887Profs*64) in KIF1A. Segregation analysis revealed that this mutation was homozygous in all five affected individuals of the family with severe clinical manifestation, while members of the family that were heterozygous carriers shared abnormal skin features (scaly skin) only with the homozygous affected members.
Conclusions: A novel frameshift mutation p.(Ser887Profs*64) in KIF1A is the potential cause of severe HSANIIC in a Pakistani family along with incomplete penetrance in mutation carriers. We demonstrate that using a combination of different techniques not only strengthens the gene finding approach but also helps in proper sub-clinical characterization along with identification of mutated alleles exhibiting incomplete penetrance leading to intrafamilial clinical variability in HSAN group of inherited diseases.
摘要：
背景：遗传性感觉和自主神经病变（HSANs）是由周围神经退化引起的罕见异质性神经系统疾病。HSAN亚临床类别具有临床和遗传重叠，这通常导致误诊。在本研究中，对一个巴基斯坦家庭的五名受影响成员患有严重的神经病变进行了遗传分析，以确定该家庭中的致病因素。方法：进行全基因组高密度单核苷酸多态性（SNP）微阵列分析，然后对受影响的先证者和另一个受影响的同胞进行全外显子组测序。通过纯合性作图方法鉴定了所有严重受影响成员中的共享纯合区域。结果：在2号染色体上鉴定了该家族的五个严重受影响的成员共有的最大的14.1Mb纯合区域。随后的外显子组测序鉴定了KIF1A中的新的单核苷酸缺失c.2658del;p.(Ser887Profs*64)。分离分析显示，该突变在具有严重临床表现的家庭中所有五个受影响的个体中都是纯合的，而杂合携带者家族成员仅与纯合受累成员共享异常皮肤特征（鳞状皮肤）。结论：KIF1A中的新型移码突变p。（Ser887Profs*64）是巴基斯坦家庭中严重HSANIIC的潜在原因，以及突变携带者的不完全外显率。我们证明，使用不同技术的组合不仅可以增强基因发现方法，而且还可以帮助进行适当的亚临床表征，以及鉴定表现出不完全外显率的突变等位基因，从而导致HSAN遗传性疾病组的家族内临床变异性。
