Peter John

A mutation in the lipase H (LIPH) gene underlie autosomal recessive hypotrichosis

Hereditary hypotrichosis is a rare autosomal recessive disorder characterized by sparse hair on scalp and rest of the body of affected individuals. Two forms of such hypotrichosis LAH and AH have been mapped on chromosome 18q12.1 and 3q27, respectively. Mutations in desmogelin 4 (DSG4) gene have been reported to underlie LAH. Recently, a deletion mutation in Lipase H (LIPH) gene, located at AH locus, has been identified in two ethnic groups of Russian population. In the present study, a four generation Pakistani family with AH phenotype has been mapped to chromosome 3q27. Sequence analysis of candidate gene LIPH revealed a novel five base pair deletion mutation (c.346–350delATATA) in exon 2 of the gene leading to frameshift and downstream premature termination codon. The mutation reported in the family, presented here, is the second mutation identified in LIPH gene. The identification of a genetic defect in LIPH suggests that this enzyme regulates hair growth.

Previously described sequence variant in CDK5RAP2 gene in a Pakistani family with autosomal recessive primary microcephaly

BackgroundAutosomal Recessive Primary Microcephaly (MCPH) is a disorder of neurogenic mitosis. MCPH leads to reduced cerebral cortical volume and hence, reduced head circumference associated with mental retardation of variable degree. Genetic heterogeneity is well documented in patients with MCPH with six loci known, while pathogenic sequence variants in four respective genes have been identified so far. Mutations in CDK5RAP2 gene at MCPH3 locus have been least involved in causing MCPH phenotype.MethodsAll coding exons and exon/intron splice junctions of CDK5RAP2 gene were sequenced in affected and normal individuals of Pakistani MCPH family of Kashmiri origin, which showed linkage to MCPH3 locus on chromosome 9q33.2.ResultsA previously described nonsense mutation [243 T>A (S81X)] in exon 4 of CDK5RAP2 gene has been identified in the Pakistani family, presented here, with MCPH Phenotype. Genomic and cDNA sequence comparison revealed that the exact nomenclature for this mutation is 246 T>A (Y82X).ConclusionRecurrent observation of Y82X mutation in CDK5RAP2 gene in this Pakistani family may be a sign of confinement of a rare ancestral haplotype carrying this pathogenic variant within Northern Pakistani population, as this has not been reported in any other population.

Localization of a novel locus for alopecia with mental retardation syndrome to chromosome 3q26.33–q27.3

Alopecia with mental retardation syndrome is a rare autosomal recessive disorder characterized clinically by total or partial alopecia and mental retardation. In an effort to understand the molecular bases of this form of alopecia syndrome, large Pakistani consanguineous kindred with multiple affected individuals has been ascertained from a remote region in Pakistan. Genome wide scan mapped the disease locus on chromosome 3q26.33–q27.3. A maximum two-point LOD score of 3.05 (θ=0.0) was obtained at marker D3S3583. Maximum multipoint LOD score exceeding 5.0, obtained with several markers, supported the linkage. Recombination events observed in affected individuals localized the disease locus between markers D3S1232 and D3S2436, spanning 11.49-cM region on chromosome 3q26.33–q27.3. Sequence analysis of a candidate gene ETS variant gene 5 from DNA samples of two affected individuals of the family revealed no mutation.

Recurrent intragenic deletion mutation in desmoglein 4 gene underlies autosomal recessive hypotrichosis in two Pakistani families of Balochi and Sindhi origins

Localized autosomal recessive hypotrichosis (LAH) is rare disorder affecting the scalp, trunk and extremities and largely sparing the facial, pubic and axillary hair. Mutations in desmoglein 4 (DSG4) gene are responsible for LAH which maps to human chromosome 18q12. In this study a recurrent intragenic deletion mutation (Ex5_8del) was identified in DSG4 gene in two Pakistani families of Balochi and Sindhi origins. Manifestation of identical intragenic deletion mutation in eight Pakistani families, six reported earlier and two here, is exceptionally evocative of the dispersion of ancestral chromosome in different ethnic groups through common ancestors.

Localization of a novel autosomal recessive hypotrichosis locus (LAH3) to chromosome 13q14.11–q21.32

Autosomal recessive hypotrichosis is a rare form of alopecia characterized by sparse hair on scalp, sparse to absent eyebrows and eyelashes, and sparse auxiliary and body hair. Previously, for this form of hypotrichosis, two loci LAH (localized hereditary hypotrichosis) and AH (autosomal recessive hereditary hypotrichosis) have been mapped on chromosome 18q12.1 and 3q27.2, respectively. In the study presented here, we report the localization of a third locus for autosomal recessive form of hypotrichosis in two large Pakistani families. The patients in the two families exhibited typical features of the hereditary hypotrichosis. Genome scan using polymorphic microsatellite markers mapped the gene on chromosome 13q14.11–q21.32. A maximum combined two‐point logarithm of odds (LOD) score of 4.79 at θ= 0.0 was obtained for several markers. Multipoint linkage analysis resulted in a maximum LOD score of 5.9, which further supports the linkage. Haplotype analysis defined the linkage interval of 17.35 cM flanked by markers D13S325 and D13S1231 according to the Rutgers combined linkage‐physical map. This region contains 24.41 Mb according to the build 36 of the human genome sequence‐based physical map.

Atrichia with papular lesions in two Pakistani consanguineous families resulting from mutations in the human hairless gene

Atrichia with papular lesions (APL) is a rare autosomal recessive form of total alopecia, characterized by hair loss soon after birth and the development of papular lesions of keratin-filled cysts over extensive areas of the body. Mutations in the hairless (hr) gene, a putative single zinc finger transcription factor, have been implicated in the pathogenesis of this disorder. In the present study, we describe two novel deletion mutations in exons 2 and 8 of the human hairless gene leading to frameshift and downstream premature termination codons in two consanguineous Pakistani families affected with atrichia.

A novel locus for alopecia with mental retardation syndrome (APMR2) maps to chromosome 3q26.2-q26.31

Congenital alopecia may occur either alone or in association with ectodermal and other abnormalities. On the bases of such associations, several different syndromes featuring congenital alopecia can be distinguished. Alopecia with mental retardation syndrome (APMR) is a rare autosomal recessive disorder, clinically characterized by total or partial hair loss and mental retardation. In the present study, a five‐generation Pakistani family with multiple affected individuals with APMR was ascertained. Patients in this family exhibited typical features of APMR syndrome. The disease locus was mapped to chromosome 3q26.2‐q26.31 by carrying out a genome scan followed by fine mapping. A maximum two‐point logarithm of odds (LOD) score of 2.93 at θ= 0.0 was obtained at markers D3S3053 and D3S2309. Multipoint linkage analysis resulted in a maximum LOD score of 4.57 with several markers, which supports the linkage. The disease locus was flanked by markers D3S1564 and D3S2427, which corresponds to 9.6‐cM region according to the Rutgers combined linkage‐physical map of the human genome (build 35) and contains 5.6 Mb. The linkage interval of the APMR locus identified here does not overlap with the one described previously; therefore, this locus has been designated as APMR2.

Mapping of a Gene for Alopecia with Mental Retardation Syndrome (APMR3) on Chromosome 18q11.2-q12.2

Alopecia with mental retardation syndrome (APMR) is a rare autosomal recessive disorder characterized by total or partial absence of hair from the scalp and other parts of the body and associated with mental retardation. Previously, we have reported the mapping of two alopecia and mental retardation genes (APMR1 and APMR2) on human chromosome 3. In the present study, after excluding both of these loci through linkage analysis, a whole genome scan was performed by genotyping 396 polymorphic microsatellite markers located on 22 autosomes and the X and Y chromosomes. A disease locus was mapped to a 10.9 cM region, flanked by markers D18S866 and D18S811, on chromosome 18q11.2–q12.2. A maximum two‐point LOD score of 3.03 at θ= 0.0 was obtained with marker D18S1102. Multipoint linkage analysis resulted in maximum LOD scores of 4.03 with several markers in the candidate region. According to the Rutgers combined linkage‐physical map of the human genome (build 36) this region covers 12.17 Mb. DNA sequence analysis of nine candidate genes including DSC3, DSC1, DSG1, DSG4, DSG3, ZNF397, ZNF271, ZNF24 and ZNF396 did not reveal any sequence variants in the affected individuals of the family presented here.

The mapping of DFNB62, a new locus for autosomal recessive non-syndromic hearing impairment, to chromosome 12p13.2-p11.23.

Autosomal recessive non‐syndromic hearing impairment (ARNSHI) is the most common form of prelingual inherited hearing impairment (HI). Here is described the mapping of a novel ARNSHI locus in a consanguineous Pakistani family with profound congenital HI. Two‐point and multipoint linkage analyses were performed for the genome scan and fine mapping markers. Haplotypes were constructed to determine the region of homozygosity. At θu2003=u20030, the maximum two‐point LOD score of 4.0 was obtained at marker AAC040. A maximum multipoint LOD score of 5.3 was derived at marker D12S320, with the three‐unit support interval demarcated by D12S89 and D12S1042. The region of homozygosity is flanked by markers D12S358 and D12S1042, which corresponds to 22.4u2003cM according to the Rutgers combined linkage‐physical map of the human genome and spans 15.0u2003Mb on the sequence‐based physical map. A novel ARNSHI locus DFNB62 was mapped to chromosome 12p13.2‐p11.23. DFNB62 represents the second ARNSHI locus to map to chromosome 12.

Identification of a homozygous missense mutation in LRP2 and a hemizygous missense mutation in TSPYL2 in a family with mild intellectual disability.

Non-syndromic autosomal recessive intellectual disability (ID) is a genetically heterogeneous disorder with more than 50 mutated genes to date. ID is characterized by deficits in memory skills and language development with difficulty in learning, problem solving, and adaptive behaviors, and affects ∼1% of the population. For detection of disease-causing mutations in such a heterogeneous disorder, homozygosity mapping together with exome sequencing is a powerful approach, as almost all known genes can be assessed simultaneously in a high-throughput manner. In this study, a hemizygous c.786C>G:p.Ile262Met in the testis specific protein Y-encoded-like 2 (TSPYL2) gene and a homozygous c.11335G>A:p.Asp3779Asn in the low-density lipoprotein receptor-related protein 2 (LRP2) gene were detected after genome-wide genotyping and exome sequencing in a consanguineous Pakistani family with two boys with mild ID. Mutations in the LRP2 gene have previously been reported in patients with Donnai–Barrow and Stickler syndromes. LRP2 has also been associated with a 2q locus for autism (AUTS5). The TSPYL2 variant is not listed in any single-nucleotide polymorphism databases, and the LRP2 variant was absent in 400 ethnically matched healthy control chromosomes, and is not listed in single-nucleotide polymorphism databases as a common polymorphism. The LRP2 mutation identified here is located in one of the low-density lipoprotein-receptor class A domains, which is a cysteine-rich repeat that plays a central role in mammalian cholesterol metabolism, suggesting that alteration of cholesterol processing pathway can contribute to ID.