Ideogram of chromosome 18 displaying positions of the functional genes along the linkage interval (Chr18p11.32-p11.31 on GRCH37/hg19 assembly) of 3.03 Mb identified in the family.

<p>Ideogram of chromosome 18 displaying positions of the functional genes along the linkage interval (Chr18p11.32-p11.31 on GRCH37/hg19 assembly) of 3.03 Mb identified in the family.</p

Two-point LOD score between ED syndrome and SNP markers on chromosome 18p11.32-p11.31.

<p><b>a</b> Physical positions of the SNPs are according to the dbSNP132 (<a href="http://genome.ucsc.edu/cgi-bin/hgGateway" target="_blank">http://genome.ucsc.edu/cgi-bin/hgGateway</a>)</p><p><b>b</b> Recombination fraction.</p><p>Two-point LOD score between ED syndrome and SNP markers on chromosome 18p11.32-p11.31.</p

Pedigree of a consanguineous Pakistani family segregating an autosomal recessive form of a novel type of ectodermal dysplasia.

<p>Circles and squares represent females and males, respectively. Clear symbols represent unaffected individuals while filled symbols represent affected individuals. Symbols with asterisk represent DNA samples available for the molecular analysis.</p

<i>KIF1A</i> novel frameshift variant p.(Ser887Profs*64) exhibits clinical heterogeneity in a Pakistani family with hereditary sensory and autonomic neuropathy type IIC

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.</p