Chromosomal Aberrations and Down syndrome

The conversation on 13th June2022 was initiated by Prof. P.C. Joshi on the 96th birth anniversary of Jerome Jean-Louis-Marie-Lejeune. Celebrating his contributions, he wrote: “Jerome Lejeune was passionately devoted to alleviating sufferings of those afflicted with disability caused by chromosomal aberrations. He genuinely wanted to find a cure and dedicated his life towards it. Sadly, he died of cancer on April 5, 1994 and lamented that he failed in his mission: "I was the doctor who was supposed to cure them and I am leaving. I feel like I am abandoning them". These are the golden words from a dedicated human geneticist. Today when we remember him, we must also consider completing his unfinished mission in life. Let's dedicate ourselves to wipe out the pain and misery of those suffering with chromosomal aberrations.”

Anthropomorphic forms that humans possess are subject of social construction resulting in racial discrimination, abuse, disabilities, and infirmities. These repetitive and at time normative constructs were developed without taking congruence of the fact that these are often defined by genetic structures that are quite similar, if not the same across ethnicities. All human beings across all forms of social constructions have 23 pairs of chromosomes. Out of these, the first 22 pairs are called autosomes and the last pair is called sex chromosome (X and Y) that attribute in sociological discourse gender status to an individual. In simple terms persons having the combination of XY chromosome are designated as male and those with XX combination are assigned female identity. Each parent contributes one set of 23 chromosomes to their offspring to make it 23 pairs.  It is probably a subject for another conversation to discuss, how and why this one set of chromosomal difference resulted in centuries of subjugation, distortions, and discrimination for one half of the humanity[1].

In this conversation, we will briefly discuss agonies of those marginalized often from the time of their birth and assigned the category of ‘disabled’; ‘mad’, ‘apahij’ etc. etc, connotations that mark them as a category of exclusion. Most of them are not even aware of the fact that their suffering is genetic and has nothing to do with their psychic-self or ‘past sins.’

[1] Females primarily responsible for ascertaining continuity of civilization, continue to be controlled by institutions including social, cultural, religious, and political. Most recent example of this control is abolition of right to abortion in politically democratic country like US by its Supreme Court and return of medieval governance in Afghanistan denying fundamental rights to one half of its population, comprising of women and third gender. 

SCIENCE EXPLAINS

The science behind these phenotypic variability lies in the chromosomal variation within an individual that we commonly refer to as “chromosomal aberrations.” These chromosomal aberrations and its social and biological consequences were subject of the UIAF WhatsApp conversation held on 13th June 2022.

To go back to the dialogues that experts had on the subject, let us try to understand what these aberrations or abnormalities are and what are its medical consequences.

Chromosomal abnormalities can occur as an accident when the egg or the sperm is formed or during the early developmental stages of the foetus. The age of the mother and certain environmental factors may play a role in the occurrence of genetic errors. Prenatal screening and testing can be performed to examine the chromosomes of the foetus and detect some of the chromosomal abnormalities. There are two kinds of chromosomal aberrations that generally occur. It can be either numerical or structural. A numerical abnormality (aneuploidy) means an individual is either missing one of the chromosomes from a pair (monosomy) or has more than two chromosomes instead of a pair (trisomy). A structural abnormality means the chromosome's structure has been altered in one of several ways that includes deletion, duplication, inversion, and translocation. Following diagrammatic presentation gives a synoptic view of these aberrations:

 The most common examples of these chromosomal disorders are Down’s syndrome, Klinefelter syndrome, and Turner syndrome. Let us discuss the syndromes one by one.

Down syndrome is a genetic disorder in which a person has an extra chromosome. In 1959 Jerome Lejeune, Marthe Gautier, and M. Raymond Turnip discovered that Down Syndrome patients have an extra chromosome. Typically, a child is born with 46 chromosomes (23 pair of chromosomes) while children born with Down syndrome exhibit an extra copy of chromosome 21, which made one of the pair a triplet (trisomy 21). Down's syndrome causes a distinct facial appearance, intellectual disability, and developmental delays. It may also be associated with thyroid or heart disease. It is one of the most commonly occurring chromosomal abnormalities in India having an incidence of 1 per 700-800 live births. However, early intervention programmes with a team of therapists and special educators who can treat each child's specific situation are helpful in managing Down's syndrome.

This is defined as trisomy 21 because of the presence of an extra chromosome 21. Its phenotypic manifestation is in various forms like Bushfield spots seen as white/grey spots at the edge of the Iris; may cause dysmorphic feature, most often observed in the form of a flat face or atypically small head. It may also cause gastrointestinal problems causing frequent vomiting, neuromuscular issues because of decreased muscle tone; cardiovascular problems causing shortness of breath, pale skin, and fatigue.

In addition to Down syndrome, there are two other autosomal trisomy’s on chromosome 18 causing Edwards syndrome and trisomy 13 triggering Patau Syndrome.

Edward syndrome causes severe mental disability, large back of the head, clenched hands, a small mouth, rocker bottom feet having large heels.

Patau Syndrome may result in severe intellectual disability, its physical indicators often comprise of a small head, small eyes, cleft lips or palate, rocker bottom feet, polydactyly (five fingers on one hand), holoprosencephaly (malformation of the forebrain).

There are other noticeable structural aberrations among human population that include Cri-du-chat syndrome, also called cat’s cry or 5P-(5P minus) syndrome was discovered by Jerome Lejeune in 1963. The condition occurs due to the deletion on the short arm of chromosome 5. It is a rare condition, occurring in only about 1 in 20,000 to 1 in 50,000 new-borns. But it is one of the more common syndromes caused by chromosomal deletion. “Cri-du-chat” means “cry of the cat” in French. Infants with the syndrome produce a high-pitched cry that sounds like a cat. The larynx develops abnormally due to the chromosome deletion, which affects the sound of the child’s cry. The syndrome is more noticeable as the child ages, but becomes difficult to diagnose past age 2.

Charcot-Marie- Tooth disease type-I occurs because part of chromosome -17 duplicates itself causing weakness of muscles.

Another condition, Robertsonian translocations (ROBs), named after the American biologist W.R.B. Robertson, were first described in 1916 in grasshoppers. It results when two acrocentric chromosomes (having two chromosomes with unequal arm lengths due to a non-centred centromere), lose short arm of the chromosomes and the two long arms consequently conjoin that may potentially result in trisomy. 

GENDER DISTORTIONS-ANEUPLOIDES OF THE SEX CHROMOSOMES

There are Sex Chromosomal Abnormalities (SCAs) which distort the phenotypic character of a particular gender. These are the most commonly occurring chromosomal disorders, affecting 1 in 400 new-borns (Linden, Bender, & Robinson, 1995). SCAs are characterized by either gain or loss of entire sex chromosomes (aneuploidy), or parts of sex chromosomes (structural abnormalities, e.g., isochromosomes). The best-known syndromes among the SCAs are Turner syndrome (45, X), Klinefelter syndrome (47, XXY), 47, XXX syndrome and 47, XYY syndrome. Numerical aberrations of the sex chromosome may cause delayed puberty, absence of menstruation, infertility, and ambiguous genitalia.

Turner syndrome was identified in 1938 by Prof. Henry Turner in a group of females with short stature, absence of secondary sexual characteristics, and primary amenorrhea. Most of them had 45 X karyotype and others had 46nXX karyotype with a deletion in part of one X chromosome. There were also mosaics involving 45, X and 46 XX and 46, XY cells or more complex combinations. A common anthropomorphic feature in more than 80% of these individuals was short stature with average height of 148cm. Females born with Turner syndrome may live well through their lives.

Klinefelter Syndrome remains largely undiagnosed in general population. It may be diagnosed in boys with behavioural disorders. They may have abnormally small testes, and long legs. It is the presence of only long lower extremities that distinguishes people with Klinefelter Syndrome from the other forms of eunuchoidism also having equally long upper and lower extremities. People born with Klinefelter Syndrome (47, XXX and XXY) face enormous difficulties.

SOCIAL EXCLUSION AND ETHICS OF PRENATAL TESTING

One tends to assume that scientists engrossed in basic research, pursue their passion only to make discoveries that are devoid of human emotions and empathy. But reading about Lejeune along with Raymond Turnip and Martha Gautier and many other like them, brings back the faith in researchers who do research to alleviate human pain and suffering.  But what is beyond their agency is the unethical use of their knowledge and its commodification.

Decades of research on trisomy documents that advance age of mother at the time of conception carries risk of all forms of trisomy and other chromosomal aberrations. To eliminate the risk of sex chromosome aneuploidies, invasive testing is offered to women at a higher risk of trisomy linked to 21,18, 13 chromosomes. Some of these are now detectable with ultrasound findings but those not seen through ultrasound are advised to go further for a targeted diagnostic test like FISH (fluorescence in situ hybridization) or quantitative fluorescence polymerase chain reaction (QF-PCR). There is growing concurrence among the medical science fraternity that instead of frequent use of invasive technology, “testing for less” using method of Karyotyping (or recently introduced method of chromosomal microarray) is bound to be safer. [Details drawn from Guido de Wert. 2018. “Ethics of Cell-Free DNA-Based Prenatal Testing for Sex chromosome Aneuploidies and Sex determination” in Non-invasive Prenatal Testing (NIPT)].

However, what is troubling at present is the misuse of these technological tools. These tests are developed to help a pregnant woman make a choice. It is parental decision to take the risk of having a child who may have some abnormalities due to chromosomal aberrations. The opinion of experts helps prospective parents to get better counselling and avert the shock of sudden realization post birth complications of the baby. Sadly, this technology is blatantly being misused for unlawful sex determination of foetuses in countries like India. Cultural son preference often results in unlawful elimination of female foetus by unethical use of this technology.

PROFILES OF FEW SCIENTISTS PIONEERING CHROMOSOMAL ABERRATION RESEARCH

Jerome Lejeune was a famous French geneticist and paediatrician best known for his discovery of the chromosome abnormality which causes Down's syndrome. For this outstanding discovery he was awarded Kennedy prize by the then President John F. Kennedy himself. He was appointed Director of Research at the National Centre for Scientific Research, Paris in 1963, and Professor of Fundamental Genetics at the Faculty of Medicine in Paris in 1964. He was awarded the William Allan Award, the highest award given by the American Society of Human Genetics. He was also appointed as the first President of the Pontifical Academy for Life.

• In 1958, Lejeune along with Raymond Turnip and Martha Gautier discovered that Down syndrome is caused by an extra copy of chromosome (trisomy 21).

• He was the first scientist to link a human disorder (intellectual disability) with a chromosome aberration.

• He discovered the underlined mechanism of various chromosomal diseases and hence founded the discipline of cytogenetics.

• He also identified Cri du Chat syndrome (1963) caused by missing segment in the short arm of chromosome 5.

• In 1966, he described 18q-syndrome, which results from loss of the distal portion of the long arm of chromosome 18.

• He also identified Malformation syndrome in which a ring-shaped chromosome replaces chromosome 13.

Martha Gautier was a French physician and known as the co-discoverer of the chromosome aberration responsible for Down’s syndrome (trisomy 21).

Henry Hubert Turner was an American endocrinologist, noted for his published description of Turner Syndrome in 1938. He graduated in medicine from the University of Louisville School of Medicine in 1921 and served as chief of endocrinology and as associate dean of the University of Oklahoma College of Medicine. One of the founders of modern endocrinology, Turner was involved in the establishment of several endocrinological journals and in promoting research and postgraduate education in his speciality. He was for many years secretary and president of the Society for the Study of Internal Secretions.

GIST OF WATSAPP CONVERSATION ON 13th June, 2022

In order to honour and remember Jerome Lejeune (born on 13th June, 1926), a French geneticist on his 96th birth anniversary, Prof. P.C. Joshi (former acting Vice-chancellor of Delhi University and currently president of SIMA, Society for Indian Medical Anthropology) wrote:

“On June 13, we remember, Jerome-Jean-Louis-Marie-Lejeune on his 96th birth anniversary. Considered to be playing an important role in the area of chromosomal aberrations and development of cytogenetics, Lejeune along with Raymond Turnip and Martha Gautier discovered that Down Syndrome is caused by extra copy of chromosome 21 (1958). Besides Down syndrome, Lejeune identified Cri du Chat syndrome (1963) that is caused by missing segment in the short arm of chromosome 5. In 1966, he described 18q-syndrome, which results from loss of the distal portion of the long arm of chromosome 18. Besides, he discovered a malformation syndrome in which a ring-shaped chromosome replaces chromosome 13.

He was passionately devoted to alleviate sufferings of the disability caused due to chromosomal aberrations. He genuinely wanted to find a cure and dedicated his life towards it. However, he died of cancer on April 5, 1994 and acknowledged that he failed in his mission: "I was the doctor who was supposed to cure them and I am leaving. I feel like I am abandoning them".

These are the golden words from a dedicated human geneticist. Today when we remember Jerome-Jean-Louis-Marie-Lejeune, we must also consider completing his unfinished life mission. Let's dedicate ourselves to wipe out the pain and misery of sufferers of chromosomal aberrations.”

Responding to Prof. Joshi’s post, Dr. R.P. Mitra, Professor of Social Anthropology at University of Delhi remarked:

“Thank you for highlighting the contributions of Lejeune, in understanding of Chromosomal aberration and diseases. In this regard, a study carried out by the Cambridge University, published in the recent issue of the journal, 'Genetics in Medicine, reported that one in 500 men may be carrying an extra X or Y chromosome, without being even aware of it. The Cambridge team examined the DNA from 207,067 men of European ancestry aged from 40 to 70 years, enrolled with the UK Bio-bank (who tend to be healthier) and identified 231 men with an extra X chromosome and 143 men with an extra Y chromosome. Other than sexual and behavioural problems, carrying an extra chromosome also raises the risks of several medical conditions, including the risk of type 2 diabetes and blocked blood vessels in the lungs, quadrupled the risk of COPD, and raised the risk of blocked veins sixfold, the researchers reported.”

To this Dr. Kumkum Srivastava, Consultant, Society for Social Service (Former Associate Professor of History, Janaki Devi Memorial College, University of Delhi) added:

“Thanks for sharing great information. One in 500 men carrying an extra X and Y chromosomes is really alarming and its consequences are manifold.

For the last portion “let’s dedicate to wipe the pain……” Now with prenatal screening aberrations are uncommon. Moreover, if humans never faced chromosomal and genetic abnormalities that paved the path of nano evolution how would we evolve? Till Homo sapiens would survive and till “descent with modification” will be there… natural selections will happen… and so Darwinian theories will find its significance “survival of fittest”. Now with advancements of molecular anthropology we can do prognosis and restrict a formation…

Trisomy 21 is the most common of the three, occurring in 1 out of every 691 births. The disorder was first identified in 1866 by John Langdon Down, a British physician, and later named after him.”

Prof. Arup Ratan Bandyopadhyay, Professor and Former Head of the Department of Anthropology, University of Calcutta responded:

Aberrations are the forms of mutations, basically of three types: Genome, genic and gene/and or point. Genome mutation includes ploidies (aneuplodies and ployploidies). Aneuplodies are when chromosome numbers of a species in not exact multiple of the haploid numbers, such as autosomal condition, Down’s (Trisomy 21) and Patau’s syndrome (Trisomy 13). While genic mutations include structural change in chromosome (Translocation, deletion, inversion etc.). Sometimes, Down’s syndrome occurred through translocation too. In addition to that, gene mutation includes base substitution (Single nucleotide polymorphisms) to alter protein (non-synonymous mutation), if not altering the protein then synonymous mutation. Most well know example of (non-synonymous mutation) is HbS.

The etiology, of genome mutation is generally accepted as non-disjunction by anaphase lag in the cell division process which may have association with biological age. While genic mutation is caused by chromosomal breakage. All the genome mutation individuals are infertile; therefore, they are born by the normal parents.

“I fondly cherish the discussion with Prof. Srivastava regarding sex chromatin and inactivation of X chromatin as dosage compensation (Lyon hypothesis) in females, originally identified in female cat, but all the mammals show this interesting feature, which again is noteworthy as female possesses mosaic cells (activated and inactivated), may be considered as natural mosaic and natural clone too.

Since this is inactivated and late replicating, therefore it is found as cell mass (condensed) in the periphery in pre-metaphase and metaphase cell division stage in epithelium cells and easier and economising biomarker (reproductive status and even in reproductive cancer) from buccal epithelium. One of my students did her PhD in this issue and couple of research article have already been published. One student is also pursuing her PhD taking up the sex chromatin inactivation.

Just to add, Cummins (1939) the doyen of dermatoglyphics identified Down's Syndrome through finger and palm prints perhaps two decades before the karyotype confirmation.

Perhaps respected Prof. S.B. Roy (Bhagavan'da) can remember, as one of the editors, Dept. of Anthropology, Calcutta University, a small contribution on dermatoglyphic and Down's Syndrome.“

 To sum up this, Prof. SR Mondal made some observations:

“Morning messages, subsequent posts and counter posts attracted my attentions on some significant points even those are not my specialized branch of knowledge. Some Observations out of curiosity:

Lejeune, Turnip and Gautier have pioneering discovery on Chromosomal aberrations, Down syndrome, Extra copy of chromosome etc... Explanations comments given by colleagues are very interesting. Females possesses mosaic cell (activated and inactivated) Nano Evolution. Descent with modification, Natural selection etc…These are undoubtedly very thought provoking. Legendary Scientists discovered the most “important facts and issues” and left the lesions behind for further researches on those facts and issues discovered.

Through legendary scientists it is known that “the things happened.” This opens the door to think- "why things happened and how things happen and; what are the facts behind them and beyond.”

Hope in coming days more discoveries will come from our biological anthropology colleagues engaged in such types of fundamental researchers.

References:

Banerjee, A. R., S. Banerjee, A. R. Bandyopadhyay, S.C. Pal, and S.P. Banerjee. 1992. A Note on Dermatoglyphic Features of Down’s Patients. In: B. M. Reddy, S. B. Roy, & B. N. Sarkar (Eds.), Dermatoglyphics Today: Proceedings of the Int. Dermatoglyphics Conference, January 1990, Calcutta (pp. 206-208). Calcutta: IBRAD, Anthropological Survey of India, and Indian Statistical Institute.

Linden, M. G., Bender, B. G., & Robinson, A. (1995). Sex chromosome tetrasomy and pentasomy. Pediatrics, 96(4 Pt 1), 672–682.

Mukherjee, Koel; Pulamaghatta Venugopal; Malay Barman, and Arup R. Bandyopadhyay. 2014. Sex chromatin frequency variation among breast cancer patients and normal females of two reproductive stages from Bengalee Hindu females. International Journal of Biological and Medical Research 5: 4150-4155.

Mukherjee, Koyel, Diptendu Chatterjee, and Arup Ratan Bandyopadhyay. 2018.  X chromatin inactivation in menopause: a study on Hindu caste Bengalee population. Asian Journal of Medical Sciences 9(3): 41-44.

Neel, James V., and William J. Schull. 1954. Human heredity. Chicago: University of Chicago Press.

Edited By

Dr. Mithun Sikdar

Superintending Anthropologist & Head of Office

Anthropological Survey of India

Southern regional Centre, Mysore

msikdar@hotmail.com

ACKNOWLEDGMENTS

UIAF editorial team is grateful to Prof. Arup Ratan Bandyopadhyay for his invaluable inputs, irrespective of his numerous engagements and busy schedule.

Thanks are due to Dr. Dinesh Kumar, research Associate, Department of Medical Microbiology, PGIMER, Chandigarh for initially compiling UIAF WhatsApp conversations held on 13th June 2022.