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Alport Syndrome is a rare genetic disorder caused by mutations in Col4-A3/A4/A5 genes. It remains largely underdiagnosed in India, as in other Asian countries when classical clinical (Anterior lenticonus/ sensorineural hearing loss {SNHL}) or renal biopsy findings (lamellation and basket weaving of the glomerular basement membrane {GBM} ) are not found. There is a global consensus that the gold standard in diagnosis is genetic testing with Next generation sequencing. We present data on whole exome sequencing performed on a cohort of Indian patients of suspected Alport syndrome with phenotypic correlation, assessment of genetic modifiers and mimics.
Whole exome sequencing of suspected Alport patients (based on clinical or biopsy features) was performed with detailed pedigree analysis and comprehensive phenotypic evaluation (eye, ear and kidney). Kidney biopsy evaluation included light microscopy, immunofluorescence and electron microscopic evaluation. Sequencing of trios comprising proband and parents and/or siblings was performed on an Illumina platform with downstream bioinformatics analysis and variant annotation based on ACMG criteria. Analysis included Collagen typeIV-Alpha3/4/5 genes and 17 potential modifiers/mimics of Alport syndrome
Eight families with suspected Alport syndrome were included. Of the 8 probands, 5 presented with proteinuria and hematuria while 3 had proteinuria only ( 2- 3+ on dipstick). Only 4 had the classical features of Anterior Lenticonus and SNHL, one had only SNHL and 3 had no abnormality on eye/ear evaluation. In the 5 patients in whom kidney biopsy was performed, 4 showed the classical lamellation and basket weaving of thickened GBM while one only displayed long thin segments. Family history of kidney disease was present in only 3 of the cases.
On evaluation of COL4A3, A4and A5, 5 showed mutation in COL4A5 including missense mutation in 2, duplication with frameshift in 1, deletion with frameshift in 1 and a large exonic deletion in 1. These segregated with the mother in 2 cases consistent with X linked inheritance, and 1 case with asymptomatic father/sibling, while one appeared de-novo. COL4A4 homozygous mutations (1 frameshift and 1 stop gain) were noted in 2 cases, which segregated with the parent /sibling consistent with Autosomal recessive
Collagen type IV genes (Col4-A3, Col4-A4, Col4-A5) variants and modifiers presentation in tabular form
inheritance. COL4A3 heterozygous mutation was noted in 1 case (with thin basement membranes) segregating with parent/sibling consistent with Autosomal dominant inheritance. Single modifier LAMA5 was observed with uncertain significance missense variant in one X-linked case segregating with mother, remaining modifiers appeared benign in all families.
Though occasional case reports of Alport syndrome in Indian patients are noted in literature, this is the first Indian cohort with comprehensive phenotypic and genetic evaluation using a Next generation sequencing approach. Spectrum of mutations were noted with variable phenotypic presentation, underscoring the need for a low index of suspicion and availability of genetic testing for this patient group in India.