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Multiple endocrine neoplasia type 1 (MEN1) in two Asian families

Teh BT, Hii SI, David R, Parameswaran V, Grimmond S, Walters MK, et al.

Hum Genet, 1994 Nov;94(5):468-72.
PMID: 7959678 DOI: 10.1007/bf00211009

Multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant disease characterized by neoplasia of the parathyroid glands, anterior pituitary and endocrine pancreas, is rarely reported in Asian populations. The MEN1 gene, mapped to chromosome 11q13 but yet to be cloned, has been found to be homogeneous in Caucasian populations through linkage analysis. Here, two previously unreported Asian kindreds with MEN1 are described; linkage analysis using microsatellite polymorphic markers in the MEN1 region was carried out. The first kindred, of Mongolian-Chinese origin, is a multigeneration family with over 150 living members, eight of whom are affected to date. The second kindred is of Chinese origin consisting of four affected members. Linkage to chromosome 11q13 was confirmed in both kindreds, supporting evidence for genetic homogeneity. A recombination in the larger kindred localizes the gene distal to marker D11S956, consistent with its placement from previous studies. We also show that it is feasible to use these markers for predictive testing, as four gene carriers were detected in 13 family members with unknown disease status in the first kindred.

Matched MeSH terms: Lod Score*
Fulltext Linkage and association studies in a Malaysian family with autosomal recessive non-syndromic hearing loss

Farah WI, Aminuddin BS, Ruszymah BH

Malays J Pathol, 2006 Jun;28(1):23-33.
PMID: 17694956 MyJurnal

Hearing loss is a common sensory deficit in humans. The hearing loss may be conductive, sensorineural, or mixed, syndromic or nonsyndromic, prelingual or postlingual. Due to the complexity of the hearing mechanism, it is not surprising that several hundred genes might be involved in causing hereditary hearing loss. There are at least 82 chromosomal loci that have been identified so far which are associated with the most common type of deafness--non-syndromic deafness. However, there are still many more which remained to be discovered. Here, we report the mapping of a locus for autosomal recessive, non-syndromic deafness in a family in Malaysia. The investigated family (AC) consists of three generations--parents who are deceased, nine affected and seven unaffected children and grandchildren. The deafness was deduced to be inherited in an autosomal recessive manner with 70% penetrance. Recombination frequencies were assumed to be equal for both males and females. Using two-point lod score analysis (MLINK), a maximum lod score of 2.48 at 0% recombinant (Z = 2.48, theta = 0%) was obtained for the interval D14S63-D14S74. The haplotype analysis defined a 14.38 centiMorgan critical region around marker D14S258 on chromosome 14q23.2-q24.3. There are 16 candidate genes identified with positive expression in human cochlear and each has great potential of being the deaf gene responsible in causing non-syndromic hereditary hearing loss in this particular family. Hopefully, by understanding the role of genetics in deafness, early interventional strategies can be undertaken to improve the life of the deaf community.

Matched MeSH terms: Lod Score
Fulltext OFD1 is mutated in X-linked Joubert syndrome and interacts with LCA5-encoded lebercilin

Coene KL, Roepman R, Doherty D, Afroze B, Kroes HY, Letteboer SJ, et al.

Am J Hum Genet, 2009 Oct;85(4):465-81.
PMID: 19800048 DOI: 10.1016/j.ajhg.2009.09.002

We ascertained a multi-generation Malaysian family with Joubert syndrome (JS). The presence of asymptomatic obligate carrier females suggested an X-linked recessive inheritance pattern. Affected males presented with mental retardation accompanied by postaxial polydactyly and retinitis pigmentosa. Brain MRIs showed the presence of a "molar tooth sign," which classifies this syndrome as classic JS with retinal involvement. Linkage analysis showed linkage to Xpter-Xp22.2 and a maximum LOD score of 2.06 for marker DXS8022. Mutation analysis revealed a frameshift mutation, p.K948NfsX8, in exon 21 of OFD1. In an isolated male with JS, a second frameshift mutation, p.E923KfsX3, in the same exon was identified. OFD1 has previously been associated with oral-facial-digital type 1 (OFD1) syndrome, a male-lethal X-linked dominant condition, and with X-linked recessive Simpson-Golabi-Behmel syndrome type 2 (SGBS2). In a yeast two-hybrid screen of a retinal cDNA library, we identified OFD1 as an interacting partner of the LCA5-encoded ciliary protein lebercilin. We show that X-linked recessive mutations in OFD1 reduce, but do not eliminate, the interaction with lebercilin, whereas X-linked dominant OFD1 mutations completely abolish binding to lebercilin. In addition, recessive mutations in OFD1 did not affect the pericentriolar localization of the recombinant protein in hTERT-RPE1 cells, whereas this localization was lost for dominant mutations. These findings offer a molecular explanation for the phenotypic spectrum observed for OFD1 mutations; this spectrum now includes OFD1 syndrome, SGBS2, and JS.

Matched MeSH terms: Lod Score
Phytoestrogens levels determination in the cord blood from Malaysia rural and urban populations

Mustafa AM, Malintan NT, Seelan S, Zhan Z, Mohamed Z, Hassan J, et al.

Toxicol Appl Pharmacol, 2007 Jul 1;222(1):25-32.
PMID: 17490695

This study is a result of an analysis of free and conjugated phytoestrogens daidzein, genistein, daidzin, genistin and coumesterol in human cord blood plasma using LCMS. Cord blood was collected from urban and rural populations of Malaysia (n=300) to establish a simple preliminary database on the levels of the analyzed compounds in the collected samples. The study also aimed to look at the levels of phytoestrogens in babies during birth as this may have a profound effect on the developmental process. The sample clean up was carried out by solid-phase extraction using C18 column and passed through DEAE sephadex gel before analysis by LCMS. The mean concentrations of total phytoestrogens were daidzein (1.4+/-2.9 ng/ml), genistein (3.7+/-2.8 ng/ml), daidzin (3.5+/-3.1 ng/ml), genistin (19.5+/-4.2 ng/ml) and coumesterol (3.3+/-3.3 ng/ml). Distribution of phytoestrogen was found to be higher in samples collected from rural areas compared to that of urban areas.

Matched MeSH terms: Lod Score
Linkage analysis and whole exome sequencing reveals AHNAK2 as a novel genetic cause for autosomal recessive CMT in a Malaysian family

Tey S, Shahrizaila N, Drew AP, Samulong S, Goh KJ, Battaloglu E, et al.

Neurogenetics, 2019 08;20(3):117-127.
PMID: 31011849 DOI: 10.1007/s10048-019-00576-3

Charcot-Marie-Tooth (CMT) disease is a form of inherited peripheral neuropathy that affects motor and sensory neurons. To identify the causative gene in a consanguineous family with autosomal recessive CMT (AR-CMT), we employed a combination of linkage analysis and whole exome sequencing. After excluding known AR-CMT genes, genome-wide linkage analysis mapped the disease locus to a 7.48-Mb interval on chromosome 14q32.11-q32.33, flanked by the markers rs2124843 and rs4983409. Whole exome sequencing identified two non-synonymous variants (p.T40P and p.H915Y) in the AHNAK2 gene that segregated with the disease in the family. Pathogenic predictions indicated that p.T40P is the likely causative allele. Analysis of AHNAK2 expression in the AR-CMT patient fibroblasts showed significantly reduced mRNA and protein levels. AHNAK2 binds directly to periaxin which is encoded by the PRX gene, and PRX mutations are associated with another form of AR-CMT (CMT4F). The altered expression of mutant AHNAK2 may disrupt the AHNAK2-PRX interaction in which one of its known functions is to regulate myelination.

Matched MeSH terms: Lod Score
Fulltext Discovery of candidate genes for nonsyndromic cleft lip palate through genome-wide linkage analysis of large extended families in the Malay population

Mohamad Shah NS, Salahshourifar I, Sulong S, Wan Sulaiman WA, Halim AS

BMC Genet, 2016 Feb 11;17:39.
PMID: 26868259 DOI: 10.1186/s12863-016-0345-x

BACKGROUND: Nonsyndromic orofacial clefts are one of the most common birth defects worldwide. It occurs as a result of genetic or environmental factors. This study investigates the genetic contribution to nonsyndromic cleft lip and/or palate through the analysis of family pedigrees. Candidate genes associated with the condition were identified from large extended families from the Malay population.
RESULTS: A significant nonparametric linkage (NPL) score was detected in family 100. Other suggestive NPL and logarithm of the odds (LOD) scores were attained from families 50, 58, 99 and 100 under autosomal recessive mode. Heterogeneity LOD (HLOD) score ≥ 1 was determined for all families, confirming genetic heterogeneity of the population and indicating that a proportion of families might be linked to each other. Several candidate genes in linkage intervals were determined; LPHN2 at 1p31, SATB2 at 2q33.1-q35, PVRL3 at 3q13.3, COL21A1 at 6p12.1, FOXP2 at 7q22.3-q33, FOXG1 and HECTD1 at 14q12 and TOX3 at 16q12.1.
CONCLUSIONS: We have identified several novel and known candidate genes for nonsyndromic cleft lip and/or palate through genome-wide linkage analysis. Further analysis of the involvement of these genes in the condition will shed light on the disease mechanism. Comprehensive genetic testing of the candidate genes is warranted.

Matched MeSH terms: Lod Score