SEGREGATION ANALYSIS OF PAKISTANIFAMILIES WITH HERIDITARY ECTODERMAL DYSPLESIAEctodermal dysplasia:-Ectodermal dysplasia is not a single disorder, but agroup of syndromes all deriving from abnormalities of the ectodermal structures. More than 150different syndromes have been identified. Ectodermal dysplasias are described as: “heritableconditions in which there are abnormalities of two or more ectodermalstructures such as the hair, teeth, nails, sweat glands, salivary glands, cranial-facial structure, digits and other parts of thebody.”Whatcauses ED?Ectodermal Dysplasias are caused by altered genes.

Thealtered genes may be inherited or normal genes may become defective (mutate) atthe time of conception. The chances for parents to have affected childrendepend on the type of ED that exists in the family.It is important to rememberthat a person cannot choose or modify the genes that he or she has.Geneticcounseling is available for families.One common type of ED affects males more than femalesthis is the X-linked type of hypohidrotic ED, other types can affect males orfemales equally and may be inherited in different ways.Despite some of thesyndromes having different genetic causes the symptoms are sometimes verysimilar.

Diagnosis is usually by clinical observation often with the assistanceof family medical histories so that it can be determined whether transmissionis autosomal dominant or recessive.ANALYSIS IN PAKISTANI FAMILIES:-Three Pakistani families (N, O, P)displaying different types of ectodermal dysplasias have been investigated.Affected members in the family N presented a novel combination of abnormalitiesof  hair, nails and localized skinpigmentation. Affected members in the second family O showed features of purehair and nail ectodermal dysplasia (PHNED) while those in the family Pexhibited features of hypohidrotic ectodermal dysplasia (HED).

Characterization of a Familywith Abnormalities of Hair, Nail and Skin Pigmentation  Family N Subjects and Clinicalfeatures  Family N was recruited from District Nawabshah, SindhProvince, Pakistan. This five generation family has six affected individuals(IV-6, IV-8, IV-9, IV-10, IV-11, V-2) who were 12 to 28 years of age at thetime of the study. All the affected individuals are the product ofconsanguineous unions and born at full term of normal pregnancies. The pedigreeshowed clear evidence of autosomal recessive mode of inheritance.

Detailedclinical evaluation revealed following clinical features in the affected individualsof the family.Nails:At the time of birth nailgrowth was normal. Dystrophy of the nails appeared during second decade of thepatient’s life.

Severe onychodystrophy manifested.Other features associatedwith nail dystrophy noted in the patients included micronychia (small nails),transverse melanonychia (dark colored spots on nail plate) and onycholysis(detachment of the nail from nail bed).Hairs: Sparse thin scalp hair ofwoolly texture, and sparse eyebrows and eyelashes were observed in all thepatients.Skin: Reticulate pattern ofhyperpigmentation manifested in form of net like dark brown gray patches, wasobserved on different parts of the body.

Associated condition of guttatehypopigmentation was noted on some of the body parts.Sweatingand dentition was found normal in all the patients. No underlying defects inrenal, liver and other organ systems were reported.Genotype:-DNA samples from six affected (IV-6, IV-8, IV-9,IV-10, IV-11, VII-7) and eight unaffected individuals (III1, III-2, III-5,III-6, IV-4, IV-5, IV-7, IV-12) were subjected to genome wide linkage analysis.

The whole genome-wide scan was performed by genotyping SNPs microarrayanalysis. . A single run of homozygous SNP markers spanning about 3.03 Mb onchromosome 18p11.

32p11.31 were detected. candidate region of 3.

03 Mb onchromosome 18p11.32-p11.31, identified in family N, contains 16 protein codingand one long intergenic non-protein coding RNA gene.

. None of these genes werereported to cause any type of dermatosis phenotype.Subsequently exons, splicejunction sites, 5’untranslated regions (UTR) and polyadenylation site in 3′ UTRof all 17 genes were screened for potential sequence variants in two affectedand one unaffected individual of the family. Sequence analysis failed to detectany functional sequence variant whichcould be responsible for causing disease phenotypes observed in the family N.Characterization of a Family with Pure Hair and NailEctodermal Dysplasia (PHNED) Family O Subjects and Clinical Features:A four generationconsanguineous family, segregating an autosomal recessive form of PHNED, wasascertained from a village in remote region of Sindh province, Pakistan.

Thefamily O comprised of five affected individuals (II-3, III-3, III-4, IV-7,IV-8) and three of them (III-3, III-4, IV-7) underwent clinical examination.Clinicalexamination revealed presence of sparse hairs on scalp, thin eyebrows andeyelashes, and thin hairs on rest of the body parts. The hairs were fragile andeasily breakable.Dystrophic nails were observed on all fingers of hands andtoes of feet.Heterozygous carriers had normal hairs and nails and wereclinically indistinguishable from genotypically normal individuals. No other associatedabnormality in other ectodermal appendages (teeth, sweat glands) was observedin any of the three affected subjects of the family. They followed normalpattern of growth and development. Genotype:-Initially, the gene KRT85, known  to cause PHNED was screened for potentialsequence variants and they fail to detect sequence variants in KRT85.

Recently,twomutations reported in the gene HOXC13, located in HOXC cluster on chromosome12p13.11-q21.1,causing PHNED phenotype. Therefore, the same gene was thensequenced in two affected and one unaffected members of the family O. Primersequences, amplified PCR product size, Tm conditions used to amplify HOXC13and  other genes.Sequence analysisrevealed a novel homozygous 4-bp duplication in exon 1 of the gene HOXC13 inall three affected individuals of the family. This sequence change resulted insubstitution of amino acid histidine to glutamine at amino acid position 68resulting in frameshifting leading to premature termination codon.

Thisduplication mutation was present in heterozygous state in obligate carriers ofthe family.Characterizationof a Family with Hypohidrotic Ectodermal Dysplasia (HED) FamilyP Subjectsand Clinical Features:Family P segregating  HED  phenotypes, is inhabitant of an area neardistrict Bhimbar in Azad Jammu and Kashmir, Pakistan. It is a small familycomprising of only one affected male individual (IV-1) who was of 24 years ofage at the time of study.

The patient demonstrated clinical symptoms compatiblewith HED clinical picture. The clinical features observed included sparse thinhypopigmented hairs on scalp, sparse eyebrows and eyelashes, absence ofaxillary, pubic and body hairs, missing frontal teeth reduced to absentsweating,dry and thin skin.Genotype:-Initially, genotyping was performedusing microsatellite markers tightly linked to four genes reported earlier tobe involved in causing HED. These included EDAR on chromosome 2q11-q13,EDA onXq12-q13,EDARADD on 1q42.2-q43 and TRAF6 on 11p12.Since, the genotyping resultsfailed to produce convincing linkage to any of the four genes, therefore, allthe four genes (EDAR, EDA, EDARADD, TRAF6) were sequenced in the affected andone unaffected members of the family.

Primer sequences and Tm conditions usedfor amplification of PCR products.Sequence analysis, however, failed to detectdisease causing variants in the four genes.

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