Molecular Evaluation of Joubert Syndrome and Hearing Impairment in a Patient with Ataxic Cerebral Palsy.

Joubert syndrome (JBTS) is a rare autosomal recessive or X-linked congenital brain malformation with strong genetic heterogeneity. Other neurological features of JBTS include hypotonia, ataxia, developmental delay, and cognitive impairment. Hearing loss with JBTS has been reported in the literature. We present the case of a 3.5-year-old boy born to a healthy consanguineous South Indian couple who was presented with ataxic cerebral palsy (CP) and hearing impairment; medical reports confirmed typical brain malformations of JBTS. Hearing impairment was screened by audiological assessment, which confirmed the presence of severe-profound hearing loss with outer hair cell dysfunction. Whole-exome sequencing (WES) was performed to know the molecular aspects of the condition and to detect any novel mutations. The homozygous mutation AHI1 c.2023G > A associated with JBTS type 3 and GJB2 c.71G > A mutation associated with hearing impairment were identified. Sanger sequencing was performed to validate the result and it identified heterozygous AHI1 c.2023G > A and GJB2 c.71G > A in the patient's parents. This study confirms the diagnosis of JBTS by WES helps identify the genetic causes of hereditary disorders that accelerate genetic evaluation and counseling for at-risk families.

PMM2 -CDG T237M Mutation in a Patient with Cerebral Palsy-Like Phenotypes Reported from South India.

Congenital disorder of glycosylation (CDG) is an autosomal recessively inherited disorder. Hypotonia, stroke-like episodes, and peripheral neuropathy are also associated with the condition that typically develops during infancy. The patient, a 12-year-old girl born to healthy consanguineous parents, was diagnosed with cerebral palsy as a child. The affected patient has hypotonia, inadequate speech, strabismus, and developmental delay with mild mental retardation, which are key symptoms of CDG. Whole-exome sequencing (WES) identified the known missense pathogenic variant PMM2 c.710 C > T, p.T237M in the patient coding for the phosphomannomutase 2 (PMM2) confirming molecular testing of CDG. The patient's parents carried heterozygous PMM2 c.710 C > T variants. This study highlights the importance of WES in patients with a developmental disability or other neurological conditions, which is also useful in screening risk factors in couples with infertility or miscarriage issues.

Analysis of SLC26A4 Gene in Individuals with Non Syndromic Hearing Impairment in Relation with GJB2 Associated Mutations.

Background: Hearing Loss (HL) is the most common sensory disorder. HL commonly ranges from mild to severe. Persons with HL face difficulty in hearing conversations or sounds through one ear or both ears, which impacts one's ability to interact with others. Hence it is a communicable disorder that makes people socially isolated, lonely, and frustrated. HL in children severely affects language development. The people who are referred to as 'Deaf' with very little or no hearing capabilities, are considered as having profound hearing loss. More than 124 genes are causative for Non-Syndromic HL (NSHL) with varying inheritance, among which the SLC26A4 mutations are the second commonest cause of hereditary HL across the globe. Methods: Samples from 70 NSHL patients were analyzed through Next-Generation Sequencing (NGS) and generated five pathogenic variants [N246fs (rs918684449), K564fs (rs746427774), F122fs, V239D (rs111033256), T721M (rs121908363)] each with frequency of 1.42%. Three missense variants [S399P (rs747431002), L597S (rs55638457), and G6V (rs111033423)] were reported under the "uncertain" category. All the collected samples were further genotyped to look for the possibility of having GJB2 and HL-associated mutations. Results: Out of five SLC26A4 pathogenic mutations N246fs (rs918684449) and K564fs (rs746427774) were observed in samples which were positive for GJB2-HL associated candidate mutations [W24X (rs104894396), Q124X (rs397516874) and W77X (rs80338944)]. Similarly, pathogenic variants F122fs, V239D (rs111033256) and T721M (rs121908363) were observed in patient samples which were negative for GJB2-HL associated mutations. Conclusion: Our data will expand the list of variants underlying NSHL and encourage further genotype SLC26A4 gene concerning the south Indian population with a large sample size.

In-situ clustering of mtDNA haplogroup M inferred from complete mitogenomes of two tribal populations of Southern India.

This study reports the mitochondrial DNA haplogroup M diversity in two tribal populations of South India. The aim of this study was to analyze and establish a mitochondrial profile to know the genetic origin and relatedness of people of India. MtDNA variability of the complete mitochondrial genome was analyzed by the Sanger sequencing method. Our results revealed novel sub-lineages of haplogroup: M2, M3, M6, M35, M65, and an M* lineage, indicating a deep in-situ origin and spread of haplogroup M lineages in India, shared with many tribal and caste populations.

Maternal genetic link of a south Dravidian tribe with native Iranians indicating bidirectional migration.

Background: The phylogeny of major mitochondrial DNA haplogroups has played a key role in assessing the people of India through molecular genetics. Aim: To resolve the phylogeny and phylogeographic pattern of autochthonous haplogroup R with its descendant haplogroup U in the Urali Kuruman tribal population of Southern India. Subjects and methods: Complete mitogenome sequences of 40 individuals were amplified and sequenced using the Sanger sequencing method. Mutations were scored referring to the revised Cambridge reference sequence, and phylogenetic trees were constructed using previously described sequences. Results: Novel sub-lineages of haplogroup R30: R30a1c1, and U1: U1a1c1d2, U1a1c1d2a were identified. Urali Kurumans pooled ancestry with the native Iranians sharing the sub-haplogroups R30a1c and U1a1c1d. The coalescence ages estimated for the sub-haplogroup R30a1c dates ∼ 9.4 ± 3.5 Kya and for subclade U1a1c1d dates ∼ 9.1 ± 2.7 Kya. Conclusion: The study revealed a genetic link between Iran and South Asia in the Neolithic time, indicating bidirectional migration and admixture.

Correction to: Neolithic phylogenetic continuity inferred from complete mitochondrial DNA sequences in a tribal population of Southern India.

Unfortunately, the original version of this article was published with an error in the second sentence of the 'Molecular dating' section.

Neolithic phylogenetic continuity inferred from complete mitochondrial DNA sequences in a tribal population of Southern India.

The subsequent human migrations that dispersed out of Africa, both prehistoric and historic and colonization of India by modern humans is unanimous, and phylogeny of major mitochondrial DNA haplogroups have played a key role in assessing the genetic origin of people of India. To address more such events, complete mitogenomes of 113 Melakudiya tribe of Southern India were sequenced and 46 individuals showed the presence of west Eurasian autochthonous haplogroups HV14 and U7. Phylogenetic analysis revealed two novel subclades HV14a1b and HV14a1b1 and sequences representing haplogroup U7 were included under previously described subclade U7a3a1a2* specific to India. Moreover, the present analysis on complete mtDNA reveals addition information of the spread and distribution of west Eurasian haplogroups in southern India, in tracing an unexplored genetic link between Melakudiya tribe with the people of Iranian Plateau, South Caucasus, and Central Asia. Coalescence ages of HV14 and U7a3a1a2* trees in the present study dates ~ 16.1 ± 4.3 and ~ 13.4 ± 5.6 kya respectively.