Lineage of Dissent

A series of studies commissioned to understand various genetic disorders revealed stunning realities that genetically Kashmir gene pool is hugely closer to Turkish, Iranian and Pakistan ethnicities. While the results may help doctors to understand certain key health crisis, these path-breaking revelations gave new direction to the ethnicity debate that is central to Kashmir’s distinct identity, reports Saima Bhat

Ghulam Qadir was lucky to survive a deadly genetic disorder, cystic fibrosis (CF). The lung infection had led him to a serious breathing problem. He was coughing up mucus and nose polyps with sinusitis.

CF, the disease which comes with more than 90 percent morbidity, is an inherited autosomal recessive disease, doctors say. It is caused by the presence of mutations in both copies of the gene for the cystic fibrosis trans-membrane conductance regulator (CFTR) protein. This protein is involved in the production of sweat, digestive fluids, and mucus. “When CFTR is not functional, secretions which are usually thin instead become thick,” senior doctors handling the crisis, said.

Three years back, Qadir was a part of a research study, Identification of Unique Pattern of CFTR gene mutations in cystic fibrosis in an ethnic Kashmiri Population by Dr Arshad Pandith. The study was focused around CFTR mutations variations in several ethnic groups and geographic areas.

To the surprise of researchers, Qadir and other patient’s genes matched with the genes with the patients suffering from the same disease in Turkey and other Central Asian countries.

The study found that out of the 150 suspected cases of CF, 24 percent of the sample study population was consistent with certain regions like Turkey, Tunisia and Iran. The frequency of this mutation in Turkish population was in complete agreement with the population under study (24.5 percent Turkey versus 24 percent population under study) but in slight agreement with Iranian population (17.8 percent in Iran versus 24 percent Kashmiri population).

“Half the time Kashmir was under lock-down and yet there were no farmer suicides or malnutrition cases – moreover, the cheeks of people were laal laal gulaabi. I want to understand where is the money coming from.” But at the same time, these studies offer the unfair side of Kashmir’s fair outlook, the morbidity of it.

 

In contrast, a high frequency of a particular mutation to produce mis-processed or misfolded proteins is found in European and other populations exceeding more than 50 percent.

The researchers have also found an androgen insensitivity syndrome, in which one Y chromosome gets defect and dislocates itself, like in ambiguous genitals disorder, where the sex of the newborn is not known. Pandith discusses this sample pattern, with a bit of variance, in a vast section of ethnicities from Kashmir to Kishtwar, Pakistan administered Kashmir and Gilgit matches with many central Asian countries like Iran, Turkey.

“We have found the same pattern of genes, which means we don’t belong to India genetically,” Pandith’s study reads. “Both have the different set of genes. In most of our studies, Kashmiri population matches with Turkey, Iran, and Pakistan.”

To an extent, the revelations by these researchers might have addressed the prime time questions by the anchors: “Half the time Kashmir was under lock-down and yet there were no farmer suicides or malnutrition cases – moreover, the cheeks of people were laal laal gulaabi. I want to understand where is the money coming from.” But at the same time, these studies offer the unfair side of Kashmir’s fair outlook, the morbidity of it.

These revelations were an interesting outcome of a study that was aimed at analyzing a different situation: genetic disorders. Researchers in endocrinology and immunology and molecular medicine departments at SKIMS, Soura, have found most of the genetic disorders are on the rise in Kashmir. The genetic disorders are reported from consanguineous, in relation couples, across the world. But in Kashmir, various researchers have found that such patients come equally from cousin marriages as well as in non-cousin marriages.

Nazia, 10, is a third standard student. Her cousin, Hareem, has just started her formal education. But in comparison, both look of same age. Her parents, not related to each other before marriage, consulted a doctor. A few gene tests later, she was diagnosed with Congenital Adrenal Hyperplasia (CAH).

CAH is also an autosomal recessive disorder, resulting from the deficiency of one of the five enzymes required for the synthesis of cortisol hormone in the adrenal glands, on kidneys.

In Kashmir, researchers say, most common CAH is steroid 21 hydroxylase deficiency caused by the alteration in a particular gene, CYP21 gene. The deficiency can affect the body’s general health, growth, and development by controlling energy levels, sugar levels, blood pressure, and body’s response to illness or injury. It can lead to vomiting due to salt-wasting, dehydration and ultimately the patient dies if not treated in time.

Kashmiri Identity

In the deficiency of other adrenal hormones, the patient’s normal growth and development can suffer. In case of excessive androgens, boys can have functional and average sized genitals but they cannot produce children due to sperm absence and girls also become infertile. In extreme cases, it can also lead to ambiguous genitalia.

After various tests, Nazia was diagnosed with losing salts from her body that would generally lead to vomiting. She was put on steroid medication. Earlier patients with salt-losing would eventually die, due to dehydration.

“Population under study (Kashmiri) remains conserved through generations as we do not prefer to marry outside our ethnic group and the majority of the population are consanguine marriages,” the paper reads. “Identification of mutations in this particular gene in Kashmiri populations, however, remains poor defined as there has been no study till this date.

Another researcher Mahruk H Zargar along with her team were jubilant when they studied the reasons behind this disease in Kashmir. “In Kashmir, the gene pool has remained conserved for centuries because Kashmiris don’t marry outside their faith and region,” their research paper Molecular Identification of Intron 2 Splice Mutation and 8bp Deletion in CYP21 Gene for Congenital Adrenal Hyperplasia (CAH) patients in Kashmir reads. “They don’t marry beyond the territory of Kashmir which means the majority of the population is consanguine marriage.”

In absence of any study of the disorders in consanguineous marriages, this study was done to understand mutations in a particular gene, CYP21. A lot of gene variations were reported in CAH patients, which usually come with the symptoms of salt losing, in several ethnic groups and geographic areas.

“Population under study (Kashmiri) remains conserved through generations as we do not prefer to marry outside our ethnic group and the majority of the population are consanguine marriages,” the paper reads. “Identification of mutations in this particular gene in Kashmiri populations, however, remains poor defined as there has been no study till this date. Keeping this in view, we conducted a preliminary CYP21 gene analysis in a group of patients suspected with CAH for two common mutations splice mutation in intron 2 is a frequent mutation, in which an A or C, at 659 and 8bp deletion in exon 3 by ARMS PCR that can discriminate between mutation and wild-type sequences, whereas pseudo gene was excluded by selective amplification.”

This study observed the gene mutation, INT2S mutation; the present is same with the report on INT2S mutation in the Turkish population. “Kashmiri genes are similar to Turkish, Pakistan and Iranian genes,” found the researchers.

The frequency of this gene mutation in Turkish population is in complete agreement with Kashmiri population under study (22 percent Turkey versus 22 percent Kashmir population under study). It is slight agreement with other populations:28 percent Iranian, and 27 percent Pakistani.“The frequency of this mutation in our group including all classic patients was ironically 0 percent in the study of CAH which is contrasting to the previous study also which to some extent resemble us like Iranian population,” research reads.

Excessive CAH disorder cases lead to ambiguous genitals in newborns. In the SKIMS lawns, Rafiq Ahmad was stunned to move beyond a point. Holding hands of his wife Shaheena, 35, he looked pale, numb and sweat was visibly tickling from his forehead. He was not coming out of the shock that his wife’s genes have revealed that she was actually a male with ambiguous genitals.

Married for more than five years, Rafiq was unable to make out anything out of the revelation. The couple was discussing how to inform their families that they are both males. And finally, they came up to the conclusion that it should remain a secret.

The couple landed in SKIMS OPD when Shaheena started developing certain health issues. They consulted a doctor and after a few tests, Shaheena was diagnosed with germ cell tumour. But the doctor sent the couple to Advanced Centre for Human Genetics in the hospital premises for Shaheena’s karyotyping test, to identify and evaluate the chromosomes.

At genetic centre, Shaheena gave her sample and the first shock was felt by the pathologist who saw the result. And when he discussed the test results with the concerned doctor, he (doctor) doubted the outcome.

They discussed this particular case repeatedly as the couple had informed they were parenting four children. The pathologist was asked to go for another advanced test, a molecular test of the chromosomes and it was again proved that Shaheena was a male and finally the couple came to take their test reports.

The first question Rafiq was asked by the pathologist was if they really have four children. And the response brought the doctors a bit of respite: “Four children by the second wife.”

Genital ambiguity is a rare genetic disorder, caused by defects in the process of fetal sex determination and differentiation where a newborn needs prompt evaluation to detect lethal conditions and gender assignments.

The main factor influencing the sex determination of an embryo, unborn human, is the genetic sex determined by the presence or absence of the Y chromosome. As a general rule, XY embryos become males and XX embryos become females. In genital ambiguity, some individuals carry a Y chromosome but are apparently females or have a female chromosome but are apparently males.

Shaheena’s doctor was now discussing what their next step should be. “We can’t say Shaheena was a perfect male but we could have driven him to the right gender had we known the status early with some hormone therapy or constructive surgeries,” her doctor said. But not to the knowledge of doctor’s Shaheena and Rafiq had decided not to come for follow-ups.

In most of such cases of genital ambiguity, quite a few patients come for follow-ups. It is difficult for them to disclose after ten or twenty years that their daughter is actually a son or vice versa. The only cases which turn up are the ones whose kid is not more than a few months old, says a pathologist.

A research Molecular and cytogenetic evaluation of gender in patients born with ambiguous genitalia from different regions of the valley of Kashmir, north India by DrArshid A Pandith and his colleagues was done on 50 ambiguous genitalia cases from a time period between 2012 and 2015 in SKIMS.

Of all the patients, 42 percent were detected as males and rest of the 58 percent were detected as females after undergoing different tests on their chromosomes.

The patients were brought up either as females or as toddlers whose sex was undetermined. Almost 80 percent of patients were not from in-relation (non-consanguineous) marriages and only twenty percent were from consanguineous (in-relation) marriages.

Muhammad Altaf, a paediatrician, informed Kashmir Life that patients with genital ambiguity are mostly treated as females by their families and it is very rare that parents consult a doctor.

“Parents treat it as a curse when they don’t know the sex of their child,” Dr Altaf said. “And this is the reason even after helping them to know the right sex of their child; they don’t turn up for follow-ups. They mostly say how can we tell our relatives that after 10 or 15 years our son is a daughter or vice versa.”

Ambiguous genitalia is a social and medical emergency and it needs prompt evaluation to detect life-threatening conditions such as the salt-losing crisis in CAH and gender assignment, medical practitioners say.

The genetic disorder is a serious situation but people link it with myths. Doctors believe it is very difficult to tell anybody that their child is having a genetic problem. “They don’t accept it as their whole family is labelled as genetically diseased, we have to remain very cautious,” one doctor said.

Mehmood and Nafia, first cousins are married for nearly three decades now. They have three sons, two of them are blinds and the youngest is physically fit but he is having difficulty in learning.

“My eldest son was born perfectly alright. But once he was nine years old he started losing vision. He had to undergo a number of surgeries but we couldn’t save his vision. The second was born blind and the third is not mentally fit,” says Nafia, 45.

Asked if she knows why it has happened with her children, Nafia has a quick response: “My parents say I am cursed by God. Before getting married I along with my parents visited Ajmer Sharif but I don’t believe in shrines or faith healers so I preferred to stay out. My mother says it might have annoyed the saint of the Shrine.”

Experts believe the prevalence of Down’s syndrome is increasing possibly because of late marriage with higher maternal age as the strength of egg decreases after 35 years. “We have also found that interrelation marriages play an important role in the prevalence of these genetic disorders.”

Initially, Nafia didn’t pay attention to her mother but when all of her kids were having certain defects, she started visiting all faith healers as well as the shrines. Even that couldn’t help her.

For all these years, Nafia has been crying for the fate of her children. She and her husband later took their two visually impaired sons to Dehradun, where they were admitted to a special school in the late nineties.

“Not only they have memorised the Holy Quran but they were trained for special computer and typewriting courses as well. Both of them have got good jobs and have started earning.” Nafia feels contended with her decision as she feels her sons won’t be dependent on anyone. But her youngest son is giving her tough time as he has dropped out of the school. “Nobody can understand what I am going through to see all of my kids like this.”

Off late, the researchers have found other genetic disorders are on the rise in the world. Every year at least two percent children are born with genetic disorders and same is the case in Kashmir, where researchers believe the prevalence of Down’s syndrome has increased.

Farooq Ahmad and Naseema are married for two decades now. The couple has three children, two daughters, both normal and a son, Umar, 11, who is having Down’s syndrome.

For all these years, Farooq and his family accused Naseema of not taking her pregnancy seriously when she was expecting Umar. “My kids were toddlers so I had to take them on my lap while sleeping. And I had to do every work in the kitchen. Taking rest was not possible.” Naseema delivered Umar when she must have been in her early forties.

Experts believe the prevalence of Down’s syndrome is increasing possibly because of late marriage with higher maternal age as the strength of egg decreases after 35 years. “We have also found that interrelation marriages play an important role in the prevalence of these genetic disorders.”

Naseema and her husband live a modest life, have visited many faith healers so that Umar could talk and could control his urine. They use diapers for him and most often they can’t afford this “luxury”.

As per a research, done on 462 suspected cases of different chromosomal abnormalities between 2011 and 2013 from the different regions of Kashmir, 82 cases (17.75 percent) were having abnormal chromosomes and rest of the 380 cases (82.25 percent) were found to be normal.

Out of the abnormal chromosomes, 11.04 percent were having Down’s syndrome, 4.11 percent had Turner’s syndrome (a chromosomal disorder in which a female is born with only one X chromosome), 1.95 percent had Klinefelter’s syndrome (a genetic condition that results when a boy is born with an extra copy of the X chromosome), 0.43 percent had Robertsonian translocation (a rare form of chromosomal rearrangement where the participating chromosomes break at their centromeres and the long arms fuse to form a single, large chromosome with a single centromere), 0.22 percent had Triple X chromosome and 0.98 percent had ambiguous genitalia.

Earlier children with Down’s syndrome used to live up to 10 to 12 years only as they had less immunity and 10 percent of them had a hole in their heart. But with advances in technology such patient’s life expectancy has increased.

Doctors believe that if patients with Down’s syndrome can be trained specially as per their requirement, they too can excel in their lives and can integrate socially and be productive.

(All names of patients, parents and the kids have been deliberately changed.)