Musharraf Jelani

A novel deletion mutation in LIPH gene causes autosomal recessive hypotrichosis (LAH2)

Autosomal recessive hypotrichosis is a rare hereditary disorder characterized by sparse hair on scalp and rest of the body of affected subjects. Recently, three clinically similar autosomal recessive forms of hypotrichosis [localized autosomal recessive hypotrichosis (LAH)1], LAH2 and LAH3 have been mapped on chromosomes 18q12.1, 3q27.3, and 13q14.11‐q21.32, respectively. For these three loci, two genes DSG4 for LAH1 and LIPH for LAH2 have been identified. To date, only five mutations in DSG4 and two in LIPH genes have been reported. In this study, we have ascertained two large unrelated consanguineous Pakistani families with autosomal recessive form of hypotrichosis. Affected individuals showed homozygosity to the microsatellite markers tightly linked to LIPH gene on chromosome 3q27. Sequence analysis of the gene in the affected subjects from both the families revealed a novel deletion mutation in exon 5 (c.659‐660delTA) causing frameshift and downstream premature termination codon. All the three mutations identified in the LIPH gene, including the one in this study, are deletion mutations.

A novel splice-site mutation in the CDH3 gene in hypotrichosis with juvenile macular dystrophy

Background.  Hypotrichosis with juvenile macular dystrophy (HJMD) is a rare autosomal recessive disorder characterized by sparse hair on the scalp and early blindness. Mutations in the CDH3 gene have been reported to underlie HJMD.

Mutations in the P2RY5 gene underlie autosomal recessive hypotrichosis in 13 Pakistani families.

Background  Autosomal recessive hypotrichosis is a rare genetic irreversible hair loss characterized by sparse scalp hair, sparse to absent eyebrows and eyelashes, and sparse axillary and body hair. Affected male individuals have normal beard hair.

Exome analysis identified a novel missense mutation in the CLPP gene in a consanguineous Saudi family expanding the clinical spectrum of Perrault Syndrome type-3

Perrault syndrome (PRLTS) is a clinically and genetically heterogeneous disorder. Both male and female patients suffer from sensory neuronal hearing loss in early childhood, and female patients are characterized by premature ovarian failure and infertility after puberty. Clinical diagnosis may not be possible in early life, because key features of PRLTS, for example infertility and premature ovarian failure, do not appear before puberty. Limb spasticity, muscle weakness, and intellectual disability have also been observed in PRLTS patients. Mutations in five genes, HSD17B4, HARS2, CLPP, LARS2, and C10orf2, have been reported in five subtypes of PRLTS. We discovered a consanguineous Saudi family with the PRLTS3 phenotype showing an autosomal recessive mode of inheritance. The patients had developed profound hearing loss, brain atrophy, and lower limb spasticity in early childhood. For molecular diagnosis, we complimented genome-wide homozygosity mapping with whole exome sequencing analyses and identified a novel homozygous mutation in exon 6 of CLPP at chromosome 19p13.3. To our knowledge, early onset with regression is a unique feature of these PRLTS patients that has not been reported so far. This study broadens the clinical spectrum of PRLTS3.

Mutation in PVRL4 gene encoding nectin-4 underlies ectodermal-dysplasia-syndactyly syndrome (EDSS1)

Ectodermal-dysplasia-syndactyly syndrome (EDSS1) is a rare form of ectodermal dysplasia (ED), affecting skin and its appendages mainly hair, teeth and nails. In the present study, we have investigated a large consanguineous Pakistani family with 10 individuals showing features of EDSS1. Human genome was screened using highly polymorphic microsatellite markers to identify the gene causing EDSS1. The disease locus for EDSS1 was assigned to chromosome 1q23.1-q23.3. This region corresponds to 5.63 Mb according to the sequenced based physical map (Build 36.2) of the human genome and flanked by markers D1S1653 and D1S1677. A maximum two-point LOD score of 5.05 was obtained with the marker D1S484. Sequence analysis revealed a homozygous missense mutation (c.635C>G; p.Pro212Arg) in the recently reported PVRL4 gene causing EDSS1. The involvement of mutant nectin-4 in causing EDSS1 may open up interesting prospectives into the role of cell adhesion molecules in causing syndromic forms of EDs.

Mutation Analysis of the ASPM Gene in 18 Pakistani Families With Autosomal Recessive Primary Microcephaly

Autosomal recessive primary microcephaly (MCPH) is a rare neurological disorder, in which the patients exhibit reduced occipital frontal head circumference (>3 standard deviations) and mild-to-severe mental retardation. Autosomal recessive primary microcephaly is genetically heterogeneous and 7 loci have been reported to date. Mutations in ASPM (abnormal spindle-like, microcephaly associated) gene are the most common cause of autosomal recessive primary microcephaly in the majority of the reported families. In the current investigation, we have located and studied 21 families with autosomal recessive primary microcephaly. Genotyping using polymorphic microsatellite markers linked to 7 autosomal recessive primary microcephaly loci revealed linkage of 18 families to the MCPH5 locus. Sequence analysis of the ASPM gene in 18 linked families detected 2 novel nonsense mutations (c.2101C>T/p.Q701X; c.9492T>G/p.Y3164X) in 2 families and 2 novel deletion mutations (c.6686delGAAA/p.R2229TfsX9; c.77delG/p.G26AfsX41) in 2 other families. Three previously described mutations (c.3978G>A/p.W1326X; c.1260delTCAAGTC/p.S420SfsX32; c.9159delA/p.K3053NfsX4) were also detected in 11 families. These identified mutations extended the body of evidence implicating the ASPM gene in the pathogenesis of human hereditary primary microcephaly.

Digenic inheritance of an autosomal recessive hypotrichosis in two consanguineous pedigrees

Basit S, Wali A, Aziz A, Muhammad N, Jelani M, Ahmad W. Digenic inheritance of an autosomal recessive hypotrichosis in two consanguineous pedigrees.

Whole exome analysis reveals a novel missense PNPLA1 variant that causes autosomal recessive congenital ichthyosis in a Pakistani family

Autosomal recessive congenital ichthyosis (ARCI) is a major class of ichthyosis, which includes harlequin ichthyosis, congenital ichthyosiform erythroderma and lamellar ichthyosis [1]. More or less generalized dryness, hyperkeratosis, scaling, redness, blister formation and the inability to sweat characterize hereditary ichthyosis [2]. The signs and symptoms vary in different types of ichthyosis. In these disorders, there is no mucosal or extracutaneous involvement, and they are classified as disorders of keratinization or cornification [3]. Pathologically, a desquamation defect prefigures the disease, with underlying keratinocytes differentiation anomalies or metabolic malfunctioning [4], which leads to the characteristic excessive scaling of the skin. Disease severity ranges from very mild manifestations to life threatening conditions, which relate not only to the heterogeneity of the genes involved, but also to the variable pathogenicity of the underlying mutations, modifying genes and environmental factors [5]. As reviewed recently, ARCI is associated with mutations in nine genes, including ABCA12, ALOXE3, ALOX12B, CERS3, CYP4F22, LIPN, NIPAL4, PNPLA1 and TGM1 [6]. We enrolled a large consanguineous family (Fig. 1a) residing in a remote village of the Swat valley, Khyber Pakhtunkhwa Province, Pakistan. Written informed consent was obtained from the study participants themselves or from the legal parents/guardians of children. The study was approved by the Institutional Review Board (IRB) of Quaid-i-Azam University (Islamabad, Pakistan) and Sungshin Women’s University (Seoul, South Korea), following research and ethics standards according to the Helsinki Declaration. All the affected individuals exhibited the non-bullous congenital ichthyosiform erythroderma phenotype of ARCI. The babies were covered with a collodion membrane at birth. They had diffused red ichthyosis and were covered with fine whitish scales. The scaling was present on almost 90% of their body surface area and affected the scalp, forehead, face, neck, chest, abdomen, back, inter-scapular region, arms, forearms, thighs, legs and dorsal aspects of the hands and feet, although it was more prominent on certain body parts, e.g., the neck, groins, hands and forearms. Features, such as keratoderma of the palms and soles, fissuring of the palms and soles, loss of eyebrows and ectropion, were not observed in these individuals. They had hyper linear palms and soles. Nails were normal in all the affected individuals. Younger individuals presented with mild facial lesions and thick adherent scales on their scalps. The condition improved slightly with age, which was noticed more as in cases having extra personal care. All of these individuals could sweat, but perhaps to a lesser degree compared with individuals with an intact stratum corneum barrier. Symptoms of the disease tended to be more severe during the winter.

Case of Sjögren–Larsson syndrome with a large deletion in the ALDH3A2 gene confirmed by single nucleotide polymorphism array analysis

Sjögren–Larsson syndrome (SLS) is a neurocutaneous disorder inherited in an autosomal recessive fashion. SLS patients are characterized by lipid metabolism error, primarily leading to cardinal signs of ichthyosis, spasticity and mental retardation. Additional signs include short stature, epilepsy, retinal abnormalities and photophobia. More than 90 mutations of the ALDH3A2 gene have been reported for SLS, and such variants can be successfully detected at a rate of 94% by direct DNA sequencing. We performed direct sequencing of ALDH3A2 gene from the index patient, however, no mutation could be detected. HumanCytoSNPs12 array analysis and subsequent targeted single nucleotide polymorphism analysis revealed a novel deletion mutation at chromosome 17p11.2. This 67‐Kb region includes the first five coding exons of ALDH3A2, and is flanked by rs2245639 and rs962801. To the best of our knowledge, this mutation is novel and our findings broaden the mutation spectrum of ALDH3A2 causing SLS phenotype.

Novel nonsense mutation in the PTRF gene underlies congenital generalized lipodystrophy in a consanguineous Saudi family.

Congenital generalized lipodystrophies (CGLs) are a heterogeneous group of rare, monogenic disorders characterized by loss of sub-cutaneous fat, muscular hypertrophy, acanthosis nigricans, hepatomegaly, cardiac arrhythmias, impaired metabolism and mental retardation. Four different but overlapping phenotypes (CGL1-4) have been identified, which are caused by mutations in AGPAT2 at 9q34.3, BSCL2 at 11q13, CAV1 at 7q31.1, and PTRF at 17q21.2. In this study, we performed genome-wide homozygosity mapping of two affected and one unaffected subject in a Saudi family using a 300K HumanCytoSNPs12v12.1 array with the Illumina iScan system. A common homozygous region at chromosome 17q22.1, from 34.4 to 45.3 Mb, was identified in both the affected individuals. The region is flanked by SNPs rs139433362 and rs185263326, which encompass the PTRF gene. Bidirectional DNA sequencing of the PTRF gene covering all of the coding exons and exon-intron boundaries was performed in all family members. Sequencing analysis identified a novel homozygous nonsense mutation in the PTRF gene (c.550G>T; p.Glu184*), leading to a premature stop codon. To the best of our knowledge, we present a novel mutation of PTRF from Saudi Arabia and our findings broaden the mutation spectrum of PTRF in the familial CGL4 phenotype. Homozygosity mapping coupled with candidate gene sequencing is an effective tool for identifying the causative pathogenic variants in familial cases.