The molecular landscape of ASPM mutations in primary microcephaly.

BACKGROUND: Autosomal recessive primary microcephaly (MCPH) is a model disease to study human neurogenesis. In affected individuals the brain grows at a reduced rate during fetal life resulting in a small but structurally normal brain and mental retardation. The condition is genetically heterogeneous with mutations in ASPM being most commonly reported. METHODS AND RESULTS: We have examined this further by studying three cohorts of microcephalic children to extend both the phenotype and the mutation spectrum. Firstly, in 99 consecutively ascertained consanguineous families with a strict diagnosis of MCPH, 41 (41%) were homozygous at the MCPH5 locus and all but two families had mutations. Thus, 39% of consanguineous MCPH families had homozygous ASPM mutations. Secondly, in 27 non-consanguineous, predominantly Caucasian families with a strict diagnosis of MCPH, 11 (40%) had ASPM mutations. Thirdly, in 45 families with a less restricted phenotype including microcephaly and mental retardation, but regardless of other neurological features, only 3 (7%) had an ASPM mutation. This report contains 27 novel mutations and almost doubles the number of MCPH associated ASPM mutations known to 57. All but one of the mutations lead to the use of a premature termination codon, 23 were nonsense mutations, 28 deletions or insertions, 5 splicing, and 1 was a translocation. Seventeen of the 57 mutations were recurrent. There were no definitive missense mutations found nor was there any mutation/phenotype correlation. ASPM mutations were found in all ethnic groups studied. CONCLUSION: This study confirms that mutations in ASPM are the most common cause of MCPH, that ASPM mutations are restricted to individuals with an MCPH phenotype, and that ASPM testing in primary microcephaly is clinically useful.

Mutations in WNT7A cause a range of limb malformations, including Fuhrmann syndrome and Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome.

Fuhrmann syndrome and the Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome are considered to be distinct limb-malformation disorders characterized by various degrees of limb aplasia/hypoplasia and joint dysplasia in humans. In families with these syndromes, we found homozygous missense mutations in the dorsoventral-patterning gene WNT7A and confirmed their functional significance in retroviral-mediated transfection of chicken mesenchyme cell cultures and developing limbs. The results suggest that a partial loss of WNT7A function causes Fuhrmann syndrome (and a phenotype similar to mouse Wnt7a knockout), whereas the more-severe limb truncation phenotypes observed in Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome result from null mutations (and cause a phenotype similar to mouse Shh knockout). These findings illustrate the specific and conserved importance of WNT7A in multiple aspects of vertebrate limb development.

Cancer by negative heterosis: breast and ovarian cancer excess in hybrids of inbred ethnic groups.

Breast and ovarian cancer rates in Pakistan are significantly higher than in neighboring countries. The cancer rate discrepancies cannot be explained with discrepancies of their risk factors. We propose that observed cancer excess in Pakistan is due to cancer development by negative heterosis. Heterosis occurs when a hybrid has a phenotypic characteristic significantly different from that in either parent (hybrid vigor). At a molecular level, heterosis occurs in a heterozygote when one of the two alleles is inactivated. Gene inactivation occurs by methylation of cytosine in a promoter region of a gene. Initiation of allele inactivation is linked to the factors like stress, gender, diet, or another gene. In heterozygote, inactivation of one of the two tumor-suppressor alleles leads to monoallelic expression. This increases cancer risk in the same way the risk is increased in individual who inherit a single mutated tumor-suppressor gene (hereditary cancer syndrome). In both, cancer by heterosis and inherited cancer syndrome, cancer develops after inactivation of a second allele (second hit hypothesis). In a population, conditions that favor development of cancer by heterosis are those that favor mating of a large number of different homozygotes because they produce a large number of different heterozygotes. Among a large number of heterozygotes, there is an increased chance that some of hybrids will develop cancer by heterosis. In Pakistan, conditions were favorable for cancer development by heterosis because country has a high number of different ethnic groups and brotherhoods all of which have a higher rate of homozygosity due to a high frequency of consanguineous marriages, and marriages between members of different groups occurred because of intense population mixing. Result was birth of a large number of inter-ethnic/brotherhood hybrids (heterozygotes), some of which have developed cancer by heterosis.

Natural history of cardiac involvement in geleophysic dysplasia.

Geleophysic dysplasia is an autosomal recessive short-limbed, dysmorphic syndrome. The condition is frequently associated with cardiac valvular disease, which may result in secondary hypertrophy and cardiac failure. We describe two distantly related Pakistani children with classical features of geleophysic dysplasia. Pulmonary stenosis was recognized in both within a few months of birth. The younger child shows no signs of cardiac decompensation at the age of 7 years whilst her older cousin has developed a significant pulmonary gradient requiring surgical intervention in the second decade of life. The natural history of his disorder highlights that the cardiac involvement seen in apparently stable forms of geleophysic dysplasia is frequently progressive.

Transcultural genetic counselling in the UK.

OBJECTIVES: Transcultural genetic counselling is not about being an expert on any given culture, rather it is a way of thinking about patients that acknowledges and values culture. Transcultural genetic counselling aims to provide a service, and to focus attention on aspects of the genetic counselling process which can easily be overlooked as we strive to improve the ways in which complex genetic information is delivered to all of the cultural groups we seek to serve. SUBJECTS AND METHODS: Two specific examples to illustrate particular problems will be given: (1) a UK Pakistani family with a lethal skin disorder and Down syndrome diagnosed prenatally, and (2) a Caucasian family who presented with a twin pregnancy and a history of infertility. RESULTS AND DISCUSSION: This article examines the way in which patients perceive and try to make sense of genetic diseases, the information given, and the course of action taken which may play a part in this process. We are also interested in how clinicians imagine the manner in which different cultures may influence the way they interact with patients. Genetic counsellors who view these differences as positive attributes will be most likely to meet, and resolve, the challenges that arise in transcultural genetic counselling.

Aicardi-Goutières syndrome displays genetic heterogeneity with one locus (AGS1) on chromosome 3p21.

We have studied 23 children from 13 families with a clinical diagnosis of Aicardi-Goutières syndrome. Affected individuals had developed an early-onset progressive encephalopathy that was characterized by a normal head circumference at birth, basal ganglia calcification, negative viral studies, and abnormalities of cerebrospinal fluid comprising either raised white cell counts and/or raised levels of interferon-alpha. By means of genomewide linkage analysis, a maximum-heterogeneity LOD score of 5.28 was reached at marker D3S3563, with alpha=.48, where alpha is the proportion of families showing linkage. Our data suggest the existence of locus heterogeneity in Aicardi-Goutières syndrome and highlight potential difficulties in the differentiation of this condition from pseudo-TORCH (toxoplasmosis, rubella, cytomegalovirus, and herpes simplex virus types 1 and 2) syndrome.

A third novel locus for primary autosomal recessive microcephaly maps to chromosome 9q34.

Primary autosomal recessive microcephaly is a clinical diagnosis of exclusion in an individual with a head circumference >/=4 SDs below the expected age-and-sex mean. There is associated moderate mental retardation, and neuroimaging shows a small but structurally normal cerebral cortex. The inheritance pattern in the majority of cases is considered to be autosomal recessive. Although genetic heterogeneity for this clinical phenotype had been expected, this has only recently been demonstrated, with the mapping of two loci for autosomal recessive primary microcephaly: MCPH1 at 8p and MCPH2 at 19q. We have studied a large multiaffected consanguineous pedigree, using a whole-genome search, and have identified a third locus, MCPH3 at 9q34. The minimal critical region is approximately 12 cM, being defined by the markers cen-D9S1872-D9S159-tel, with a maximum two-point LOD score of 3.76 (recombination fraction 0) observed for the marker D9S290.

Primary autosomal recessive microcephaly (MCPH1) maps to chromosome 8p22-pter.

Primary (or "true") microcephaly is inherited as an autosomal recessive trait and is thought to be genetically heterogeneous. Using autozygosity mapping, we have identified a genetic locus (MCPH1) for primary microcephaly, at chromosome 8p22-pter, in two consanguineous families of Pakistani origin. Our results indicate that the gene lies within a 13-cM region between the markers D8S1824 and D8S1825 (maximum multipoint LOD score of 8.1 at D8S277). In addition, we have demonstrated the genetic heterogeneity of this condition by analyzing a total of nine consanguineous families with primary microcephaly.

Familial aplasia/hypoplasia of pelvis, femur, fibula, and ulna with abnormal digits in an inbred Pakistani Muslim family: a possible new autosomal recessive disorder with overlapping manifestations of the syndromes of Fuhrmann, Al-Awadi, and Raas-Rothschild.

We describe four affected children belonging to a large, highly inbred Muslim family originating from the North West Frontier Province of Pakistan. All children have a similar pattern of skeletal abnormalities, including aplasia/hypoplasia of the ulnae, hypoplasia of the pelvis, aplasia/hypoplasia of the femora, fibular aplasia, and variable digital abnormalities and absent/dysplastic nails. The phenotype overlaps with the syndromes of Fuhrmann, Al-Awadi, and Raas-Rothschild. The present and previously reported families probably share the same geographic and racial origin, indicating a common genetic basis of the reported skeletal abnormalities in these limb-pelvis aplasia and hypoplasia syndromes. A possibility of a new autosomal recessive syndrome in the present family cannot be excluded. Further delineation and molecular studies are required to clarify the genetic cause and phenotypic variation in Fuhrmann, Al-Awadi, and Raas-Rothschild syndromes.

A new locus for non-syndromal, autosomal recessive, sensorineural hearing loss (DFNB16) maps to human chromosome 15q21-q22.

Non-syndromal, recessive deafness (NSRD) is the most common form of inherited deafness or hearing impairment in humans. NSRD is genetically heterogeneous and it has been estimated that as many as 35 different loci may be involved. We report the mapping of a novel locus for autosomal recessive, non-syndromal deafness (DFNB16) in three consanguineous families originating from Pakistan and the Middle East. Using multipoint analysis (HOMOZ/MAPMAKER) a maximum combined lod score of 6.5 was obtained for the interval D15S1039-D15S123. Recombination events and haplotype analysis define a 12-14 cM critical region between the markers D15S1039 and D15S155 on chromosome 15q15-q21.

Linkage studies of non-syndromic recessive deafness (NSRD) in a family originating from the Mirpur region of Pakistan maps DFNB1 centromeric to D13S175.

Autosomal recessive non-syndromal hearing impairment (NSRD) is genetically heterogeneous. Five loci have been identified to date which map to chromosomes 13 (DFNB1), 11 (DFNB2), 17 (DFNB3), 7 (DFNB4) and 14 (DFBN5). We report definite linkage of NSRD to the locus DFNB1 in a single family of 27 families studied of Pakistani origin. Haplotype analysis of markers in the pericentromeric region of chromosome 13q revealed a recombination event which maps DFNB1 proximal to the marker D13S175 and in the vicinity of D13S143.

Familial microcephaly with normal intelligence in a patient with acute lymphoblastic leukemia.

The authors describe a family with two children with microcephaly and normal intelligence, in which acute lymphoblastic leukemia developed in one of the siblings. An autosomal recessive pattern of inheritance is suggested by the pedigree. This is consistent with the literature, which the authors reviewed. All of the patients have similar phenotypic features, with some demonstrating chromosomal instability. It is important to recognize this syndrome because of the increased risk of lymphoreticular malignancy.

Autosomal recessive hypoparathyroidism with renal insufficiency and developmental delay.

Four children (two boys and two girls) with hypoparathyroidism, renal insufficiency, and developmental delay are described. They were the products of consanguineous marriages in three related Asian families presenting over a six year period. All the children died within the first 15 months of life despite treatment. Postmortem examination on one child showed absent parathyroid glands. We believe these children represent a previously undescribed syndrome that appears to be inherited in an autosomal recessive manner.