Human Developmental Anomalies Research Articles

Mapping phenotypes to language: a proposal to organize and standardize the clinical descriptions of malformations

Recent developments in molecular biology have markedly speeded the processes involved in determining the molecular etiology of human Mendelian disorders. Nowhere are these changes more evident than in the field that is variously termed molecular dysmorphology, human morphogenesis, or human developmental biology. In contrast to the rapid changes in molecular genetics analysis, the processes and approaches of the clinical component of molecular dysmorphology have not changed substantially, and clinical analysis is therefore becoming relatively slower than molecular discovery. If clinical discovery is to maintain its deserved position at the forefront of human genetics research, new methods must be developed to acquire, archive, and analyze these data. The limitations of current phenotyping, specifically, the limitations of the collection and archiving of clinical data in medical journal case reports and case series manuscripts are demonstrated. Several provocative approaches that have been proposed to advance the field of clinical analysis are reviewed. Lastly, a specific proposal for a system of clinical analysis and archiving of data on human pleiotropic developmental anomaly syndromes is proposed to address these limitations.

PAX6 haploinsufficiency causes cerebral malformation and olfactory dysfunction in humans.

PAX6 is widely expressed in the central nervous system. Heterozygous PAX6 mutations in human aniridia cause defects that would seem to be confined to the eye. Magnetic resonance imaging (MRI) and smell testing reveal the absence or hypoplasia of the anterior commissure and reduced olfaction in a large proportion of aniridia cases, which shows that PAX6 haploinsuffiency causes more widespread human neuro developmental anomalies.

Mutation of a gene encoding a putative chaperonin causes McKusick-Kaufman syndrome.

McKusick-Kaufman syndrome (MKKS, MIM 236700) is a human developmental anomaly syndrome comprising hydrometrocolpos (HMC), postaxial polydactyly (PAP) and congenital heart disease (CHD). MKKS has been mapped in the Old Order Amish population to 20p12, between D20S162 and D20S894 (ref. 3). Here we describe the identification of a gene mutated in MKKS. We analysed the approximately 450-kb candidate region by sample sequencing, which revealed the presence of several known genes and EST clusters. We evaluated candidate transcripts by northern-blot analysis of adult and fetal tissues. We selected one transcript with widespread expression, MKKS, for analysis in a patient from the Amish pedigree and a sporadic, non-Amish case. The Old Order Amish patient was found to be homozygous for an allele that had two missense substitutions and the non-Amish patient was a compound heterozygote for a frameshift mutation predicting premature protein truncation and a distinct missense mutation. The MKKS predicted protein shows amino acid similarity to the chaperonin family of proteins, suggesting a role for protein processing in limb, cardiac and reproductive system development. We believe that this is the first description of a human disorder caused by mutations affecting a putative chaperonin molecule.

Genetic and physical mapping of the McKusick-Kaufman syndrome

McKusick-Kaufman syndrome is a human developmental anomaly syndrome comprising mesoaxial or postaxial polydactyly, congenital heart disease and hydrometrocolpos. This syndrome is diagnosed most frequently in the Old Order Amish population and is inherited in an autosomal recessive pattern with reduced penetrance and variable expressivity. Homozygosity mapping and linkage analyses were conducted using two pedigrees derived from a larger pedigree published in 1978. The PedHunter software query system was used on the Amish Genealogy Database to correct the previous pedigree, derive a minimal pedigree connecting those affected sibships that are in the database and determine the most recent common ancestors of the affected persons. Whole genome short tandem repeat polymorphism (STRP) screening showed homozygosity in 20p12, between D20S162 and D20S894 , an area that includes the Alagille syndrome critical region. The peak two-point LOD score was 3.33, and the peak three-point LOD score was 5.21. The physical map of this region has been defined, and additional polymorphic markers have been isolated. The region includes several genes and expressed sequence tags (ESTs), including the jagged1 gene that recently has been shown to be haploinsufficient in the Alagille syndrome. Sequencing of jagged1 in two unrelated individuals affected with McKusick-Kaufman syndrome has not revealed any disease-causing mutations.

Genomic structure of TBX2 indicates conservation with distantly related T-box genes.

TBX2 is a member of a recently discovered gene family of transcription factors, named T-box genes after the Brachyury or T gene. Mutations in two of these family members, TBX5 and TBX3, have recently been shown to be responsible for the congenital abnormalities associated with Holt Oram syndrome and ulnar-mammary syndrome respectively, while mutations in T-box genes in other species also result in developmental abnormalities in the tissues where the gene is normally expressed. Thus, it likely that other T-box genes are responsible for additional human developmental anomalies. Here we report the exon/intron boundaries of TBX2 and a polymorphism within intron 2 of TBX2 that should be useful for exploring the involvement of this gene in human genetic disease. We further note that the exon/intron boundaries of TBX2 are highly conserved within the T-box domain with those of both T and TBX5, as well as with a new human T-box gene and more distantly related genes from Caenorhabditis elegans and Drosophila. This observation should facilitate the analysis of the genomic structure of other members of this gene family. It is also of interest that several members of this gene family have an additional intron that is variably present within members of at least two different lineages of the T-box family. This observation has implications regarding the evolution of T-box genes.

Finding genes involved in human developmental disorders

Recent advances in the human genome initiative have accelerated positional cloning efforts toward identification of a number of genes responsible for human developmental anomalies, particularly those involving the skeletal system. Genotype/phenotype comparison and functional analysis of these genes will further elucidate pathways of normal and abnormal human development of the skeletal and other organ systems.

Chromosomally Abnormal Gametes as a Cause of Developmental and Congenital Anomalies in Humans*

ABSTRACT Human gamete chromosome studies using 702 oocytes and 15,864 spermatozoa were reviewed. These studies were chosen because they were carried out with our improved chromosomal technique, the gradual fixation‐air drying method, which has been proven to be very reliable.The incidence of aneuploidy was about eight times as high in the oocytes (11.0%) as in the spermatozoa (1.4%), whereas that of structural chromosome aberrations was three times as high in the spermatozoa (14.1%) as in the oocytes (4.7%). In the spermatozoa, segregation errors leading to aneuploidy were found randomly among eight chromosome groups (A‐G and sex chromosome). In contrast, they did not occur randomly in the oocytes. The observed frequency was significantly higher in group G and significantly lower in group A, as compared with the theoretical frequencies which were calculated according to the assumption that the segregation errors had taken place with an equal chance in each of 23 chromosomes. About 60% of the segregation errors were found to be due to so‐called nondisjunction (loss or gain of dyads) and about 40% were due to so‐called predivision (loss or gain of monads). The incidence of aneuploid oocytes increased slightly with the increase of donor age, although showing no statistical significance. The incidence of spermatozoa with structural chromosome aberrations vaned considerably from donor to donor (3.6–24.8%). However, there was no positive correlation between the occurrence of these spermatozoa and the age of donors or the habit of smoking.Incidences of chromosome aberrations in the human gametes (22.8% in oocytes and 15.5% in spermatozoa) were far higher than those in experimental animals. These seem to be associated closely with the characteristics of human reproduction and are responsible for a great part of human embryonic loss and developmental anomalies.

Developmental anomalies derived from exposure of zygotes and first-cleavage embryos to mutagens

Results of continuing studies indicate that the mouse zygote and two-cell embryo stages are a window of susceptibility in the experimental induction of congenital anomalies with certain mutagenic agents. The mechanisms by which the mutagens initiate the pathogenesis of these developmental defects are not known. However, in certain cases there is evidence that a nonconventional, perhaps epigenetic, mechanism is involved. Detailed characterization of the spectrum of anomalies induced and comparison of responses at the various stages exposed allowed classification of the mutagens generally into two groups. One group is characterized by being effective only in the early stages of zygote development and capable of producing a relatively high incidence of fetal death and hydrops. The other group affects all of the zygote stages studied as well as the two cell-embryo, but does not increase the incidence of fetal death and hydrops. Except for hydrops, chemicals in the two groups do not differ in terms of the types of anomalies present among malformed live fetuses, which bear a resemblance to a subset of common, sporadic human developmental anomalies that are of unknown etiology. This similarity raises the possibility that certain human developmental defects may have their origins in events that happen in the zygote and early pre-implantation stages.

Is Down syndrome a modern disease?

IS DOWN SYNDROME A MODERN DISEASE? E. PETER VOLPE* Down syndrome is the most common congenital disorder associated with severe mental retardation. The clinical features of this syndrome are quite distinctive and readily discernible to the untrained eye. The congenital disability is unmistakably stamped on the affected child's face: a prominent forehead, a flattened nasal bridge, a habitually open mouth, a projecting lower lip, a protruding tongue, slanting eyes, and a perceptible fold of lax skin (epicanthic fold) at the inner corner of each eye. This unique syndrome was the first human developmental anomaly to be traced to an alteration in the chromosome complement—namely, trisomy of chromosome 21 or, simply, trisomy 21. Down syndrome occurs about once in every 700 births, which means that of the approximately 10,000 births each day in the United States, 14 newborn infants are likely to be afflicted with this disability. The number of affected newborns would be higher were it not for the fact that four out of five conceptuses with trisomy 21 terminate in spontaneous abortion. This signifies great pregnancy wastage or, stated differently, strong natural selection against this particular type of chromosomally abnormal fetus. Down syndrome is so common and so apparent clinically that it is surprising, if not startling, that the condition was recognized as a distinct entity only slightly more than a century ago. The first comprehensive description of this disability was provided by John Langdon Down in a short paper published in the London Hospital Reports in 1866 [I]. Langdon Down (fig. 1) was then medical superintendent of the Earlswood Asylum for Idiots in Surrey, England, a position he held for about a decade. After leaving Earlswood, he established his own private home The author is indebted to Wilma Parrish for her tireless efforts in researching the art archives, as well as for her constructive criticism and encouragement in the preparation of this paper. The author is also indebted to Charles Hockman, George Bernard, and Lucy Andrews for their critical reading of the manuscript. *Professor of human genetics, School of Medicine, Mercer University, Macon, Georgia 31207.© 1986 by The University of Chicago. All rights reserved. 003 1-5982/86/2903-0491$01 .00 Perspectives in Biology and Medicine, 29, 3, Part 1 ¦ Spring 1986 \ 423 Fig. 1.—John Langdon Down, the London physician who in 1866 provided the first comprehensive description of the congenital disorder that now bears his name. (Courtesy of The Royal Society of Medicine.) for mentally retarded youngsters at a period in history when community interest in organizing schools for the mentally deficient finally wakened. Ironically, the disorder might not have been identified as a discrete entity had it not been for Down's unconventional approach to classifying congenital mental defects according to ethnic similarities. Langdon Down seized upon the Oriental-like slant of the eye to designate the condition as a "Mongolian type of idiocy." Notwithstanding his excursion into quasi anthropology, Langdon Down prepared a keen description of the disorder that now bears his name. I As seems to happen quite often in science, Langdon Down's article lay ignored or unappreciated until another report on the same subject appeared 10 years later. In the July 1876 issue of the Journal of Mental Science [2], John Fraser and Arthur Mitchell described the distinguishing physical characters of an apparently new class of idiots. Although these authors ostensibly were unaware of Langdon Down's paper, they too called attention to the Oriental-like appearance of the patients and pro424 I E. Peter Volpe ¦ Down Syndrome , Fig. 2.—The first pictorial illustration in the medical literature of a person affected with Down syndrome, as depicted in an article by Fraser and Mitchell in 1876 [2]. posed to describe the condition as "Kalmuc idiocy." Physically of small stature, the Kalmucks (or Kalmyks) are Mongolians who migrated to the lower Volga region of Russia. The patients described by Fraser and Mitchell clearly matched the account presented earlier by Langdon Down. The authors provided a carefully prepared illustration of the foot, which showed the gap between the hallux and second toe that we know today is characteristic of Down patients. More impressively, Fraser and Mitchell also provided the...

Pre-ovulatory and post-ovulatory overripeness.

ABSTRACTExperimental work using animal models suggests that alterations of the oocyte during either a delay of ovulation or a delay of fertilization could account for a major percentage of human birth defects. The mechanism by which detrimental changes in the oocyte occur during these delays is not known. Hormonal modifications just prior to ovulation could initiate biochemical processes in the oocyte which proceed to an abnormal sequence of events when ovulation or fertilization does not take place at the optimum time. Alternately, the oocyte may be programmed earlier in its growth phase and undergo degenerative changes if ovulation or fertilization does not occur at the programmed times. A better understanding of the mechanisms involved in both pre‐ovulatory and post‐ovulatory overripeness of the oocyte could ultimately lead to a reduction in the incidence of human developmental anomalies.