Publications by authors named "K M Girisha"

212 Publications

Understanding Exome Sequencing: Tips for the Pediatrician.

Indian Pediatr 2021 Feb 25. Epub 2021 Feb 25.

Department of Medical Genetics, Kasturba Medical College (Manipal Academy of Higher Education), Manipal, India. Correspondence to: Dr Girisha KM, Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576 104, India.

Exome sequencing is gaining popularity as a genomic test for the diagnosis of Mendelian disorders in children. It is essential for pediatricians to familiarize themselves with this technique and its interpretation. This brief review discusses some of the key components of a clinical or research report on exome sequencing for a practicing pediatrician, so as to enable them to utilize this test well and provide timely referrals to a clinical geneticist.
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February 2021

Wiedemann-Rautenstrauch syndrome in an Indian patient with biallelic pathogenic variants in POLR3A.

Am J Med Genet A 2021 Feb 8. Epub 2021 Feb 8.

Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India.

Wiedemann-Rautenstrauch syndrome (WRS; MIM# 264090) is a rare neonatal progeroid disorder resulting from biallelic pathogenic variants in the POLR3A. It is an autosomal recessive condition characterized by growth retardation, lipoatrophy, a distinctive face, sparse scalp hair, and dental anomalies. Till date, 19 families are reported with WRS due to variants in POLR3A. Here, we describe an 18 months old male child with biallelic c.2005C>T p.(Arg669Ter) and c.1771-7C>G variant in heterozygous state identified by exome sequencing in POLR3A leading to WRS phenotype. The variant c.1771-7C>G was earlier found to be associated with hereditary spastic ataxia. We emphasize on the phenotype in an Indian patient with WRS.
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http://dx.doi.org/10.1002/ajmg.a.62115DOI Listing
February 2021

A data set of variants derived from 1455 clinical and research exomes is efficient in variant prioritization for early-onset monogenic disorders in Indians.

Hum Mutat 2021 Jan 27. Epub 2021 Jan 27.

Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India.

Given the genomic uniqueness, a local data set is most desired for Indians, who are underrepresented in existing public databases. We hypothesize patients with rare monogenic disorders and their family members can provide a reliable source of common variants in the population. Exome sequencing (ES) data from families with rare Mendelian disorders was aggregated from five centers in India. The dataset was refined by excluding related individuals and removing the disease-causing variants (refined cohort). The efficiency of these data sets was assessed in a new set of 50 exomes against gnomAD and GenomeAsia. Our original cohort comprised 1455 individuals from 1203 families. The refined cohort had 836 unrelated individuals that retained 1,251,064 variants with 181,125 population-specific and 489,618 common variants. The allele frequencies from our cohort helped to define 97,609 rare variants in gnomAD and 44,520 rare variants in GenomeAsia as common variants in our population. Our variant dataset provided an additional 1.7% and 0.1% efficiency for prioritizing heterozygous and homozygous variants respectively for rare monogenic disorders. We observed additional 19 genes/human knockouts. We list carrier frequency for 142 recessive disorders. This is a large and useful resource of exonic variants for Indians. Despite limitations, datasets from patients are efficient tools for variant prioritization in a resource-limited setting.
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http://dx.doi.org/10.1002/humu.24172DOI Listing
January 2021

Bi-allelic missense variant, p.Ser35Leu in EXOSC1 is associated with pontocerebellar hypoplasia.

Clin Genet 2021 Apr 28;99(4):594-600. Epub 2021 Jan 28.

Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India.

RNA exosome is a highly conserved ribonuclease complex essential for RNA processing and degradation. Bi-allelic variants in exosome subunits EXOSC3, EXOSC8 and EXOSC9 have been reported to cause pontocerebellar hypoplasia type 1B, type 1C and type 1D, respectively, while those in EXOSC2 cause short stature, hearing loss, retinitis pigmentosa and distinctive facies. We ascertained an 8-months-old male with developmental delay, microcephaly, subtle dysmorphism and hypotonia. Pontocerebellar hypoplasia and delayed myelination were noted on neuroimaging. A similarly affected elder sibling succumbed at the age of 4-years 6-months. Chromosomal microarray returned normal results. Exome sequencing revealed a homozygous missense variant, c.104C > T p.(Ser35Leu) in EXOSC1 (NM_016046.5) as the possible candidate. In silico mutagenesis revealed loss of a polar contact with neighboring Leu37 residue. Quantitative real-time PCR indicated no appreciable differences in EXOSC1 transcript levels. Immunoblotting and blue native PAGE revealed reduction in the EXOSC1 protein levels and EXO9 complex in the proband, respectively. We herein report an individual with the bi-allelic variant c.104C>T p.(Ser35Leu) in EXOSC1 and clinical features of pontocerebellar hypoplasia type 1. Immunoblotting and blue native PAGE provide evidence for the pathogenicity of the variant. Thus, we propose EXOSC1 as a novel candidate gene for pontocerebellar hypoplasia.
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http://dx.doi.org/10.1111/cge.13928DOI Listing
April 2021

Clinically relevant variants in a large cohort of Indian patients with Marfan syndrome and related disorders identified by next-generation sequencing.

Sci Rep 2021 Jan 12;11(1):764. Epub 2021 Jan 12.

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.

Marfan syndrome and related disorders are a group of heritable connective tissue disorders and share many clinical features that involve cardiovascular, skeletal, craniofacial, ocular, and cutaneous abnormalities. The majority of affected individuals have aortopathies associated with early mortality and morbidity. Implementation of targeted gene panel next-generation sequencing in these individuals is a powerful tool to obtain a genetic diagnosis. Here, we report on clinical and genetic spectrum of 53 families from India with a total of 83 patients who had a clinical diagnosis suggestive of Marfan syndrome or related disorders. We obtained a molecular diagnosis in 45/53 (85%) index patients, in which 36/53 (68%) had rare variants in FBN1 (Marfan syndrome; 63 patients in total), seven (13.3%) in TGFBR1/TGFBR2 (Loeys-Dietz syndrome; nine patients in total) and two patients (3.7%) in SKI (Shprintzen-Goldberg syndrome). 21 of 41 rare variants (51.2%) were novel. We did not detect a disease-associated variant in 8 (15%) index patients, and none of them met the Ghent Marfan diagnostic criteria. We found the homozygous FBN1 variant p.(Arg954His) in a boy with typical features of Marfan syndrome. Our study is the first reporting on the spectrum of variants in FBN1, TGFBR1, TGFBR2, and SKI in Indian individuals.
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http://dx.doi.org/10.1038/s41598-020-80755-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804850PMC
January 2021

A dyadic approach to the delineation of diagnostic entities in clinical genomics.

Am J Hum Genet 2021 01;108(1):8-15

Section of Genetics and Metabolism, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA.

The delineation of disease entities is complex, yet recent advances in the molecular characterization of diseases provide opportunities to designate diseases in a biologically valid manner. Here, we have formalized an approach to the delineation of Mendelian genetic disorders that encompasses two distinct but inter-related concepts: (1) the gene that is mutated and (2) the phenotypic descriptor, preferably a recognizably distinct phenotype. We assert that only by a combinatorial or dyadic approach taking both of these attributes into account can a unitary, distinct genetic disorder be designated. We propose that all Mendelian disorders should be designated as "GENE-related phenotype descriptor" (e.g., "CFTR-related cystic fibrosis"). This approach to delineating and naming disorders reconciles the complexity of gene-to-phenotype relationships in a simple and clear manner yet communicates the complexity and nuance of these relationships.
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http://dx.doi.org/10.1016/j.ajhg.2020.11.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820621PMC
January 2021

Biallelic mutations in the death domain of PIDD1 impair caspase-2 activation and are associated with intellectual disability.

Transl Psychiatry 2021 01 5;11(1). Epub 2021 Jan 5.

Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8, Canada.

PIDD1 encodes p53-Induced Death Domain protein 1, which acts as a sensor surveilling centrosome numbers and p53 activity in mammalian cells. Early results also suggest a role in DNA damage response where PIDD1 may act as a cell-fate switch, through interaction with RIP1 and NEMO/IKKg, activating NF-κB signaling for survival, or as an apoptosis-inducing protein by activating caspase-2. Biallelic truncating mutations in CRADD-the protein bridging PIDD1 and caspase-2-have been reported in intellectual disability (ID), and in a form of lissencephaly. Here, we identified five families with ID from Iran, Pakistan, and India, with four different biallelic mutations in PIDD1, all disrupting the Death Domain (DD), through which PIDD1 interacts with CRADD or RIP1. Nonsense mutations Gln863* and Arg637* directly disrupt the DD, as does a missense mutation, Arg815Trp. A homozygous splice mutation in the fifth family is predicted to disrupt splicing upstream of the DD, as confirmed using an exon trap. In HEK293 cells, we show that both Gln863* and Arg815Trp mutants fail to co-localize with CRADD, leading to its aggregation and mis-localization, and fail to co-precipitate CRADD. Using genome-edited cell lines, we show that these three PIDD1 mutations all cause loss of PIDDosome function. Pidd1 null mice show decreased anxiety, but no motor abnormalities. Together this indicates that PIDD1 mutations in humans may cause ID (and possibly lissencephaly) either through gain of function or secondarily, due to altered scaffolding properties, while complete loss of PIDD1, as modeled in mice, may be well tolerated or is compensated for.
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http://dx.doi.org/10.1038/s41398-020-01158-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791037PMC
January 2021

SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling.

Am J Hum Genet 2021 01 11;108(1):115-133. Epub 2020 Dec 11.

Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy. Electronic address:

Signal peptide-CUB-EGF domain-containing protein 3 (SCUBE3) is a member of a small family of multifunctional cell surface-anchored glycoproteins functioning as co-receptors for a variety of growth factors. Here we report that bi-allelic inactivating variants in SCUBE3 have pleiotropic consequences on development and cause a previously unrecognized syndromic disorder. Eighteen affected individuals from nine unrelated families showed a consistent phenotype characterized by reduced growth, skeletal features, distinctive craniofacial appearance, and dental anomalies. In vitro functional validation studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, and their dysregulating effect on bone morphogenetic protein (BMP) signaling. We show that SCUBE3 acts as a BMP2/BMP4 co-receptor, recruits the BMP receptor complexes into raft microdomains, and positively modulates signaling possibly by augmenting the specific interactions between BMPs and BMP type I receptors. Scube3 mice showed craniofacial and dental defects, reduced body size, and defective endochondral bone growth due to impaired BMP-mediated chondrogenesis and osteogenesis, recapitulating the human disorder. Our findings identify a human disease caused by defective function of a member of the SCUBE family, and link SCUBE3 to processes controlling growth, morphogenesis, and bone and teeth development through modulation of BMP signaling.
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http://dx.doi.org/10.1016/j.ajhg.2020.11.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820739PMC
January 2021

Response to Hall et al.

Am J Hum Genet 2020 12;107(6):1188-1189

Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Brotman-Baty Institute, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Seattle Children's Hospital, Seattle, WA 98105, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ajhg.2020.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820630PMC
December 2020

Expanding the phenotype of PURA-related neurodevelopmental disorder: a close differential diagnosis of infantile hypotonia with psychomotor retardation and characteristic facies.

Clin Dysmorphol 2021 Jan;30(1):1-5

Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India.

Purine-rich element-binding protein A (PURA) encodes Pur-alpha, a transcriptional activator protein is crucial for normal brain development. Pathogenic variants in PURA are known to cause mental retardation, autosomal dominant 31, characterized by psychomotor delay, absent or poor speech, hypotonia, feeding difficulties, seizures or 'seizure-like' movements, and dysmorphism. PURA-related neurodevelopmental disorder (PURA-related NDD) result either from heterozygous pathogenic sequence variants in PURA or microdeletions spanning PURA. Singleton whole-exome sequencing (WES) was performed for the proband after a clinical diagnosis of infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF) was made. The pathogenic variant was validated by Sanger sequencing in the proband and parents. Comparison of PURA-related NDD and IHPRF was carried out. WES identified a novel, de-novo stop-gain variant c.178G>T in PURA. In addition to typical phenotype, subject also had hypersensitivity to various stimuli which was not reported in PURA-related NDD. Significant phenotypic overlap was observed in subjects with PURA-related NDD and IHPRF especially with IHPRF2, caused by biallelic pathogenic variants in UNC80. This study expands the phenotypic and mutational spectrum of PURA-related NDD. We propose PURA-related NDD to be considered as a close differential diagnosis of IHPRF.
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http://dx.doi.org/10.1097/MCD.0000000000000360DOI Listing
January 2021

Three M syndrome 2 in two Indian patients.

Am J Med Genet A 2021 02 1;185(2):614-616. Epub 2020 Nov 1.

Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India.

3-M syndrome is a rare autosomal recessive disorder, characterized by short stature, characteristic facies and absence of microcephaly and intellectual disability. 3-M syndrome 2 (MIM# 612921) is caused by biallelic disease causing variants in OBSL1. In this study, we identified two probands from two families with homozygous, c.1534 + 5G > T and compound heterozygous variants, c.35dup and c.1273dup in OBSL1, respectively. We herein highlight the clinical and molecular findings of the first reported cases from Indian ethnicity.
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http://dx.doi.org/10.1002/ajmg.a.61949DOI Listing
February 2021

Genetic disorders with central nervous system white matter abnormalities: An update.

Clin Genet 2021 Jan 20;99(1):119-132. Epub 2020 Oct 20.

Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India.

Several genetic disorders have variable degree of central nervous system white matter abnormalities. We retrieved and reviewed 422 genetic conditions with prominent and consistent involvement of white matter from the literature. We herein describe the current definitions, classification systems, clinical spectrum, neuroimaging findings, genomics, and molecular mechanisms of these conditions. Though diagnosis for most of these disorders relies mainly on genomic tests, specifically exome sequencing, we collate several clinical and neuroimaging findings still relevant in diagnosis of clinically recognizable disorders. We also review the current understanding of pathophysiology and therapeutics of these disorders.
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http://dx.doi.org/10.1111/cge.13863DOI Listing
January 2021

Trichothiodystrophy type 4 in an Indian family.

Am J Med Genet A 2020 10 17;182(10):2226-2229. Epub 2020 Aug 17.

Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India.

Trichothiodystrophy, non-photosensitive type 4 (TTD4), is a rare genetic disorder with an autosomal recessive mode of inheritance. It is characterized by coarse and brittle hair, anomalies of the tissues derived from the neuro-ectoderm (skin, hair, and nails) and intellectual disability. We herein report two male siblings aged 13 and 16 years with TTD4 and a known homozygous pathogenic variant, c.229del [p.(Arg77Glyfs*76)] in exon 1 of MPLKIP (NM_138701.3). We herein highlight the clinical and molecular findings of the first reported case of TTD4 in probands of Indian ethnicity.
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http://dx.doi.org/10.1002/ajmg.a.61794DOI Listing
October 2020

Mongolian spots in GM1 gangliosidosis: a pictorial report.

Clin Dysmorphol 2021 Jan;30(1):6-9

Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India.

GM1 gangliosidosis is a lysosomal storage disorder, characterized by psychomotor deterioration, visceromegaly, facial coarseness, retinal cherry-red spots, and skeletal abnormalities. We report six unrelated patients with GM1 gangliosidosis with extensive Mongolian spots on the trunk and extremities that provided clue to clinical diagnosis. All patients exhibited psychomotor delay, coarse facies, hepatosplenomegaly, hypotonia, and dysostosis multiplex. Four patients had retinal cherry-red spots. The condition was confirmed by identification of very low activities of beta-galactosidase enzyme in peripheral leukocytes and biallelic pathogenic variants in the GLB1 gene. We identified one novel (c.1479G>T) and two known (c.75 + 2dup and c.1369C>T) pathogenic variants in homozygous state in them. Our work ascertains extensive Mongolian spots as a diagnostic handle for early recognition of GM1 gangliosidosis. Though a known feature of GM1 gangliosidosis, considerable variation in the prevalence and ethnic differences are observed. This report illustrates the Mongolian spots pictorially in Indian patients.
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http://dx.doi.org/10.1097/MCD.0000000000000353DOI Listing
January 2021

Phenotypic diversity and genetic complexity of PAX3-related Waardenburg syndrome.

Am J Med Genet A 2020 12 29;182(12):2951-2958. Epub 2020 Sep 29.

Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India.

Waardenburg syndrome subtypes 1 and 3 are caused by pathogenic variants in PAX3. We investigated 12 individuals from four unrelated families clinically diagnosed with Waardenburg syndrome type 1/3. Novel pathogenic variants identified in PAX3 included single nucleotide variants (c.166C>T, c.829C>T), a 2-base pair deletion (c.366_367delAA) and a multi-exonic deletion. Two novel variants, c.166C>T and c.829C>T and a previously reported variant, c.256A>T in PAX3 were evaluated for their nuclear localization and ability to activate MITF promoter. The coexistence of two subtypes of Waardenburg syndrome with pathogenic variants in PAX3 and EDNRB was seen in one of the affected individuals. Multiple genetic diagnoses of Waardenburg syndrome type 3 and autosomal recessive deafness 1A was identified in an individual. We also review the phenotypic and genomic spectrum of individuals with PAX3-related Waardenburg syndrome reported in the literature.
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http://dx.doi.org/10.1002/ajmg.a.61893DOI Listing
December 2020

Untapped opportunities for rare disease gene discovery in India.

Am J Med Genet A 2020 12 10;182(12):3056-3059. Epub 2020 Sep 10.

Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.

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http://dx.doi.org/10.1002/ajmg.a.61866DOI Listing
December 2020

Bosley-Salih-Alorainy syndrome in patients from India.

Am J Med Genet A 2020 11 31;182(11):2699-2703. Epub 2020 Aug 31.

Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India.

Bi-allelic HOXA1 pathogenic variants clinically manifest as two distinct syndromes, Bosley-Salih-Alorainy syndrome (BSAS) and Athabascan brainstem dysgenesis syndrome, mainly reported in two different populations from Saudi Arabia and southwest North America, respectively. Here we report two siblings of Indian origin with BSAS phenotype caused by a novel homozygous exon 2 HOXA1 pathogenic variants.
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http://dx.doi.org/10.1002/ajmg.a.61809DOI Listing
November 2020

Roberts syndrome in an Indian patient with humeroradial synostosis, congenital elbow contractures and a novel homozygous splice variant in ESCO2.

Am J Med Genet A 2020 11 11;182(11):2793-2796. Epub 2020 Aug 11.

Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India.

Roberts syndrome (also known as Roberts-SC phocomelia syndrome) is an autosomal recessive developmental disorder, characterized by pre- and postnatal growth retardation, limb malformations including bilateral symmetric tetraphocomelia or mesomelia, and craniofacial dysmorphism. Biallelic loss-of-function variants in ESCO2, which codes for establishment of sister chromatid cohesion N-acetyltransferase 2, cause Roberts syndrome. Phenotypic spectrum among patients is broad, challenging clinical diagnosis in mildly affected individuals. Here we report a 3-year-old boy with a mild phenotype of Roberts syndrome with bilateral elbow contractures, humeroradial synostosis, mild lower limb disparity, and facial dysmorphism. Trio whole-exome sequencing identified the novel biallelic splice variant c.1673+1G>A in ESCO2 in the patient. Aberrant ESCO2 pre-mRNA splicing, reduced relative ESCO2 mRNA amount, and characteristic cytogenetic defects, such as premature centromere separation, heterochromatin repulsion, and chromosome breaks, in patient cells strongly supported pathogenicity of the ESCO2 variant affecting one of the highly conserved guanine-thymine dinucleotide of the donor splice site. Our case highlights the difficulty in establishing a clinical diagnosis in individuals with minor clinical features of Roberts syndrome and normal intellectual and social development. However, next-generation sequencing tools allow for molecular diagnosis in cases presenting with mild developmental defects.
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http://dx.doi.org/10.1002/ajmg.a.61826DOI Listing
November 2020

Mutations in MYLPF Cause a Novel Segmental Amyoplasia that Manifests as Distal Arthrogryposis.

Am J Hum Genet 2020 08 23;107(2):293-310. Epub 2020 Jul 23.

Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Brotman-Baty Institute, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Seattle Children's Hospital, Seattle, WA 98105, USA. Electronic address:

We identified ten persons in six consanguineous families with distal arthrogryposis (DA) who had congenital contractures, scoliosis, and short stature. Exome sequencing revealed that each affected person was homozygous for one of two different rare variants (c.470G>T [p.Cys157Phe] or c.469T>C [p.Cys157Arg]) affecting the same residue of myosin light chain, phosphorylatable, fast skeletal muscle (MYLPF). In a seventh family, a c.487G>A (p.Gly163Ser) variant in MYLPF arose de novo in a father, who transmitted it to his son. In an eighth family comprised of seven individuals with dominantly inherited DA, a c.98C>T (p.Ala33Val) variant segregated in all four persons tested. Variants in MYLPF underlie both dominant and recessively inherited DA. Mylpf protein models suggest that the residues associated with dominant DA interact with myosin whereas the residues altered in families with recessive DA only indirectly impair this interaction. Pathological and histological exam of a foot amputated from an affected child revealed complete absence of skeletal muscle (i.e., segmental amyoplasia). To investigate the mechanism for this finding, we generated an animal model for partial MYLPF impairment by knocking out zebrafish mylpfa. The mylpfa mutant had reduced trunk contractile force and complete pectoral fin paralysis, demonstrating that mylpf impairment most severely affects limb movement. mylpfa mutant muscle weakness was most pronounced in an appendicular muscle and was explained by reduced myosin activity and fiber degeneration. Collectively, our findings demonstrate that partial loss of MYLPF function can lead to congenital contractures, likely as a result of degeneration of skeletal muscle in the distal limb.
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http://dx.doi.org/10.1016/j.ajhg.2020.06.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413889PMC
August 2020

Identification and characterization of 30 novel pathogenic variations in 69 unrelated Indian patients with Mucolipidosis Type II and Type III.

J Hum Genet 2020 Nov 10;65(11):971-984. Epub 2020 Jul 10.

Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India.

Mucolipidosis (ML) (OMIM 607840 & 607838) is a rare autosomal recessive inherited disorder that occurs due to the deficiency of golgi enzyme uridine diphosphate (UDP)- N-acetylglucosamine-1-phosphotransferase (GlcNAc-phosphotransferase) responsible for tagging mannose-6-phosphate for proper trafficking of lysosomal enzymes to lysosomes. Variants in GlcNAc-phosphotransferase (GNPTAB (α, β subunits) and GNPTG (γ subunits) are known to result in impaired targeting of lysosomal enzymes leading to Mucolipidosis (ML) Type II or Type III. We analyzed 69 Indian families of MLII/III for clinical features and molecular spectrum and performed in silico analysis for novel variants. We identified 38 pathogenic variants in GNPTAB and 5 pathogenic variants in GNPTG genes including missense, frame shift, deletion, duplication and splice site variations. A total of 26 novel variants were identified in GNPTAB and 4 in GNPTG gene. In silico studies using mutation prediction software like SIFT, Polyphen2 and protein structure analysis further confirmed the pathogenic nature of the novel sequence variants detected in our study. Except for a common variant c.3503_3504delTC in early onset MLII, we could not establish any other significant genotype and phenotype correlation. This is one of the largest studies reported till date on Mucolipidosis II/III in order to identify mutation spectrum and any recurrent mutations specific to the Indian ethnic population. The mutational spectrum information in Indian patients will be useful in better genetic counselling, carrier detection and prenatal diagnosis for patients with ML II/III.
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http://dx.doi.org/10.1038/s10038-020-0797-8DOI Listing
November 2020

Genomic Testing for Diagnosis of Genetic Disorders in Children: Chromosomal Microarray and Next-Generation Sequencing.

Indian Pediatr 2020 06;57(6):549-554

Department of Medical Genetics, Kasturba Medical College, Manipal, India. Correspondence to: Dr Girisha KM, Professor, Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576 104, India.

Chromosomal microarray and Next-generation sequencing are two widely used genomic tests that have improved the diagnosis of children with a genetic condition. Chromosomal microarray has become a first-tier test in evaluating children with intellectual disability, multiple malformations and autism due to its higher yield and resolution. Next generation sequencing, that includes targeted panel testing, exome sequencing and whole genome sequencing ends diagnostic odyssey in 25-30% of unselected children with rare monogenic syndromes, especially when the condition is genetically heterogeneous. This article provides a review of these genomic tests for pediatricians.
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June 2020

Mutations in SREBF1, Encoding Sterol Regulatory Element Binding Transcription Factor 1, Cause Autosomal-Dominant IFAP Syndrome.

Am J Hum Genet 2020 07 3;107(1):34-45. Epub 2020 Jun 3.

Department of Dermatology, Peking University First Hospital, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, National Clinical Research Center for Skin and Immune Diseases, Beijing 100034, China. Electronic address:

IFAP syndrome is a rare genetic disorder characterized by ichthyosis follicularis, atrichia, and photophobia. Previous research found that mutations in MBTPS2, encoding site-2-protease (S2P), underlie X-linked IFAP syndrome. The present report describes the identification via whole-exome sequencing of three heterozygous mutations in SREBF1 in 11 unrelated, ethnically diverse individuals with autosomal-dominant IFAP syndrome. SREBF1 encodes sterol regulatory element-binding protein 1 (SREBP1), which promotes the transcription of lipogenes involved in the biosynthesis of fatty acids and cholesterols. This process requires cleavage of SREBP1 by site-1-protease (S1P) and S2P and subsequent translocation into the nucleus where it binds to sterol regulatory elements (SRE). The three detected SREBF1 mutations caused substitution or deletion of residues 527, 528, and 530, which are crucial for S1P cleavage. In vitro investigation of SREBP1 variants demonstrated impaired S1P cleavage, which prohibited nuclear translocation of the transcriptionally active form of SREBP1. As a result, SREBP1 variants exhibited significantly lower transcriptional activity compared to the wild-type, as demonstrated via luciferase reporter assay. RNA sequencing of the scalp skin from IFAP-affected individuals revealed a dramatic reduction in transcript levels of low-density lipoprotein receptor (LDLR) and of keratin genes known to be expressed in the outer root sheath of hair follicles. An increased rate of in situ keratinocyte apoptosis, which might contribute to skin hyperkeratosis and hypotrichosis, was also detected in scalp samples from affected individuals. Together with previous research, the present findings suggest that SREBP signaling plays an essential role in epidermal differentiation, skin barrier formation, hair growth, and eye function.
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http://dx.doi.org/10.1016/j.ajhg.2020.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332643PMC
July 2020

Recurrent 1q21.1 deletion syndrome: report on variable expression, nonpenetrance and review of literature.

Clin Dysmorphol 2020 Jul;29(3):127-131

Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India.

The clinical phenotype of 1q21.1 microdeletion syndrome is highly heterogeneous. It is characterized by dysmorphic facial features, microcephaly, and developmental delay. Several congenital defects, including cardiac, ocular, skeletal anomalies, and psychiatric or behavioural abnormalities, have also been described. Here, we report on two siblings with substantial intrafamilial phenotypic variability carrying a heterozygous deletion of the 1q21.1 region spanning a known critical genomic area (~1.35 Mb). The microdeletion was inherited from the unaffected father. Patients described here show a spectrum of clinical features, a portion of which overlap with those previously reported in patients with 1q21.1 microdeletions. In addition, we review the clinical reports of 66 individuals with this condition. These findings extend and substantiate the current clinical understanding of recurrent copy number variations in the 1q21.1 region.
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http://dx.doi.org/10.1097/MCD.0000000000000327DOI Listing
July 2020

Digital clubbing as the predominant manifestation of hypertrophic osteoarthropathy caused by pathogenic variants in HPGD in three Indian families.

Clin Dysmorphol 2020 Jul;29(3):123-126

Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal.

15-Hydroxyprostaglandin dehydrogenase is NAD-dependent catalytic enzyme involved in prostaglandin biosynthesis pathway encoded by HPGD. The pathogenic variations in HPGD cause primary hypertrophic osteoarthropathy (PHO). The objective of the present study is to identify the genetic basis in patients with digital clubbing due to PHO. We performed detailed clinical and radiographic evaluation and exome sequencing in patients from three unrelated Indian families with PHO. Exome sequencing revealed two novel, c.34G>A (p.Gly12Ser) and c.313C>T (p.Gln105*) and a known variant, c.418G>C (p.Ala140Pro) in HPGD. Herein, we add three Indian families to HPGD mutation spectrum and review the literature on variants in this gene.
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http://dx.doi.org/10.1097/MCD.0000000000000324DOI Listing
July 2020

Recurrent bi-allelic splicing variant c.454+3A>G in TRAPPC4 is associated with progressive encephalopathy and muscle involvement.

Brain 2020 04;143(4):e29

Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India.

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http://dx.doi.org/10.1093/brain/awaa046DOI Listing
April 2020

Novel variant p.(Ala102Thr) in SDHB causes mitochondrial complex II deficiency: Case report and review of the literature.

Ann Hum Genet 2020 07 2;84(4):345-351. Epub 2020 Mar 2.

Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India.

Leigh syndrome is a clinically and radiologically heterogeneous condition with approximately 75 genes, nuclear and mitochondrial, known to be implicated in its pathogenesis. Leigh syndrome due to complex II deficiency constitutes 2% to 7% of these cases. Previously, nine individuals with Leigh syndrome have been reported with pathogenic variants in SDHB, which encodes for the iron-sulfur cluster subunit of mitochondrial respiratory chain complex II. The proband presented with Leigh syndrome. Exome sequencing revealed a homozygous missense variant p.(Ala102Thr) in SDHB. In silico protein modeling of the wild-type and mutant proteins showed potentially decreased protein stability. We hereby report another individual with Leigh syndrome due to SDHB-related mitochondrial complex II deficiency and review the phenotype and genotype associated with this condition.
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http://dx.doi.org/10.1111/ahg.12377DOI Listing
July 2020

Spastic Paraplegia Type 56 in a Young Child.

Indian J Pediatr 2020 08 8;87(8):650-651. Epub 2020 Feb 8.

Neurology Division, Department of Pediatrics, Lady Hardinge Medical College and Associated Kalawati Saran Children's Hospital, New Delhi, India.

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http://dx.doi.org/10.1007/s12098-020-03195-1DOI Listing
August 2020

Biallelic c.1263dupC in DOK7 results in fetal akinesia deformation sequence.

Am J Med Genet A 2020 04 27;182(4):804-807. Epub 2019 Dec 27.

Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India.

Fetal akinesia deformation sequence (FADS) is a clinically and genetically heterogeneous condition. Pathogenic variants in DOK7 are known to cause myasthenic syndrome, congenital, 10 (MIM#254300) and, rarely (reported in a single family) lethal FADS. Herein, we describe a biallelic variant c.1263dupC in DOK7, known to cause congenital myasthenic syndrome 10, causing lethal FADS in a consanguineous family. The present report illustrates wide phenotypic variability caused by biallelic pathogenic variants in DOK7. We also describe the second family with FADS due to pathogenic variants in DOK7.
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http://dx.doi.org/10.1002/ajmg.a.61473DOI Listing
April 2020

Turner syndrome in diverse populations.

Am J Med Genet A 2020 02 19;182(2):303-313. Epub 2019 Dec 19.

Medical Genetics Branch, National Human Genome Research Institute, The National Institutes of Health, Bethesda, Maryland.

Turner syndrome (TS) is a common multiple congenital anomaly syndrome resulting from complete or partial absence of the second X chromosome. In this study, we explore the phenotype of TS in diverse populations using clinical examination and facial analysis technology. Clinical data from 78 individuals and images from 108 individuals with TS from 19 different countries were analyzed. Individuals were grouped into categories of African descent (African), Asian, Latin American, Caucasian (European descent), and Middle Eastern. The most common phenotype features across all population groups were short stature (86%), cubitus valgus (76%), and low posterior hairline 70%. Two facial analysis technology experiments were conducted: TS versus general population and TS versus Noonan syndrome. Across all ethnicities, facial analysis was accurate in diagnosing TS from frontal facial images as measured by the area under the curve (AUC). An AUC of 0.903 (p < .001) was found for TS versus general population controls and 0.925 (p < .001) for TS versus individuals with Noonan syndrome. In summary, we present consistent clinical findings from global populations with TS and additionally demonstrate that facial analysis technology can accurately distinguish TS from the general population and Noonan syndrome.
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http://dx.doi.org/10.1002/ajmg.a.61461DOI Listing
February 2020