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The utility and futility of targeted next generation sequencing for carrier detection in “At Risk” couples

Sunita Bijarnia-Mahay, Deepti Gupta, V L Ramprasad, Sakthivel Murugan, Renu Saxena, Sudha Kohli, Seiji Yamaguchi, Yosuke Shigematsu and I C Verma, Genetic Clinics 2017, January – March, Vol 10, Issue 1.

Next generation sequencing has changed the approach to genetic diagnosis and testing in recent times. The days have arrived when a molecular genetic diagnosis can be attempted even without the availability of the proband or affected person. However this requires additional strong evidence of diagnosis in the proband, such as biochemical or radiological hallmarks. Needless to say, this attempt should always be made during counseling to make the family aware of the fallacies and limitation involved due to non-availability of the sample of the proband. Since many recessive disorders are either fatal or severely debilitating and burdensome, with no easy treatment, the NGS technology has provided a much needed relief in terms of testing and prevention in family by enabling prenatal diagnosis, at least in a few cases. Encouraging results have been shown upon testing of the proband directly. However, the final word remains to be said on complete reliability of the method for carrier testing, performed without availability of the proband. We present two similar cases, of methyl malonic acidemia, where use of NGS resulted in contrasting outcomes after genetic testing for carrier status, thus highlighting the utility and the futility of the test in certain situations. While a correct identification of mutations in the first couple (in the MMAB gene) resulted in successful prenatal diagnosis and prevention of recurrence, an inability to identify the disease and mutation resulted in birth of an affected baby with MMA in the second family.

  http://iamg.in/genetic_clinics/adm/articlepdf/genevista_January_March_2017.pdf

Manitoba oculotrichoanal syndrome: First case report from India

Sai Rani Karanam, Vinay Kumar Konana, Shruthi Sreenivasaiah, Sudhakar Potti, Delhi Journal of Ophthalmology (2016).

Manitoba-oculo-tricho-anal (MOTA) syndrome is very rare syndrome characterized by aberrant hairline, eye anomalies (ocular hypertelorism, cryptophthalmos, and upper eyelid colobomas), bifid nose, omphalocele and anorectal anomalies. MOTA syndrome was first reported in 1992 in Oji-cree community from the Island Lake region of Manitoba, Canada. Till date very few cases of MOTA have been reported and none from India. We report first case of MOTA syndrome from India. A two month old male baby was brought with complaints of defect in right upper eye lid since birth. He was the second born child of a second degree consanguineously married couple at 37 weeks of gestation. On physical examination, the baby had right upper eyelid coloboma, ocular hypertelorism, bifid nose, small nasal ala and bilateral undescended testis. Investigations revealed high anorectal anomaly and right renal agenesis. Whole exome sequencing showed homozygous nonsense variation in exon 25 of the FREM1 gene that resulted in a stop codon. This case gains importance as it is the first case of MOTA being reported from India and bilateral undescended testis which was seen this case is an addition to the variable clinical spectrum of MOTA.

  http://www.djo.org.in/articles/27/2/manitoba-oculotrichoanal.html

A splice site mutation in HERC1 leads to syndromic intellectual disability with macrocephaly and facial dysmorphism: Further delineation of the phenotypic spectrum

Aggarwal S, Bhowmik AD, Ramprasad VL, Murugan S, Dalal A, Am J Med Genet A. 2016 Jul;170(7):1868-73.

We report on a sib pair of Indian origin presenting with intellectual disability, dysmorphism, and macrocephaly. Exome sequencing revealed a homozygous splice site HERC1 mutation in both probands. Functional analysis revealed use of an alternate splice site resulting in formation of a downstream stop codon and nonsense mediated decay. In the light of recent reports of HERC1 mutations in two families with a similar phenotypic presentation, this report reiterates the pathogenic nature and clinical consequences of HERC1 disruption.

  https://www.ncbi.nlm.nih.gov/pubmed/27108999

Sequencing and analysis of a South Asian-Indian personal genome

Ravi Gupta, Aakrosh Ratan, Changanamkandath Rajesh, Rong Chen, Hie Lim Kim, Richard Burhans, Webb Miller, Sam Santhosh, Ramana V Davuluri, Atul J Butte, Stephan C Schuster, Somasekar Seshagiri and George Thomas (2012). BMC Genomics, 13, 440.

With over 1.3 billion people, India is estimated to contain three times more genetic diversity than Europe. Next-generation sequencing technologies have facilitated the understanding of diversity by enabling whole genome sequencing at greater speed and lower cost. While genomes from people of European and Asian descent have been sequenced, only recently has a single male genome from the Indian subcontinent been published at sufficient depth and coverage. In this study we have sequenced and analyzed the genome of a South Asian Indian female (SAIF) from the Indian state of Kerala.

  https://bmcgenomics.biomedcentral.com/articles/10.1186/1471-2164-13-440
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