Abstracts & Publications

Bilateral renal agenesis is about as severe as congenital kidney malformation gets — it's usually fatal, and until this paper only three genes had ever been tied to it in humans (ITGA8, GREB1L, FGF20). Two families came in with babies who had bilateral renal agenesis picked up prenatally, no other malformations, consanguineous parents, and a sibling who'd died of the same thing before. That pattern points to recessive inheritance, so we went looking in the homozygous regions.

In the first family, we found a new nonsense variant in GFRA1. To see whether that was a one-off, we pulled 184 patients with renal agenesis from a shared repository and re-checked their exome or genome data — 36 of those had isolated renal agenesis, and two of them turned out to carry loss-of-function GFRA1 variants too, including a frameshift in the second family here. GFRA1 sits on the Wolffian duct and helps drive ureteric bud outgrowth — the step that builds the kidney's plumbing in the first place — which fits the phenotype well and gives families with unexplained bilateral renal agenesis a gene to test for and a firmer basis for genetic counselling.

Sialidosis comes from biallelic mutations in NEU1 and is usually split into a milder, later-onset type I and a severe, early-onset type II — with a cherry-red spot on the retina as the classic clinical clue. We put together seven unrelated, molecularly confirmed type II patients, which as far as we could tell was the largest such series reported anywhere. Alongside the cherry-red spot, we picked up an eye finding that hadn't been described before in this disease: bull's-eye maculopathy.

The genetics were the real surprise. Despite fairly different clinical pictures, all seven patients carried the exact same homozygous variant, c.679G>A (p.Gly227Arg), which suggests this is a founder mutation running through the north Indian population rather than seven coincidences. We also saw enough overlap between "type I" and "type II" presentations to argue these aren't two clean boxes but a continuum — which matters for anyone trying to counsel a family based on subtype alone.

Array CGH keeps turning up microdeletion syndromes nobody's fully mapped yet, and 5q11.2 is one of them. We saw a patient with a 7 Mb deletion at that locus who had features nobody had linked to it before — immunodeficiency, hand and foot asymmetry, joint laxity, and agenesis of the corpus callosum. Lining this case up against 13 previously reported patients let us narrow down a common critical region of 1.4 Mb (54–55.4 Mb) shared across all of them.

Fourteen genes sit in that region. One of them, IL6ST, codes for gp130, a signalling protein that a whole family of interleukins and cytokines routes through — it's involved in making both T and B lymphocytes and in producing acute-phase proteins, which makes it a strong candidate for the immunodeficiency seen in some of these patients. Between the shared phenotype and these new features, 5q11.2 microdeletion looks like it deserves recognition as its own syndrome rather than a grab-bag of deletion cases.

Larsen's syndrome shows up as dislocated large joints, unusual fingers and toes, a distinctive face, and short stature. We describe a five-month-old boy who had the core triad plus some extra findings, and exome sequencing pinned it to a novel missense variant in FLNB (c.4928C>G; p.Ala1643Gly) that hadn't been reported before.

Because the variant was new, we couldn't just point to prior evidence — we walked through protein modelling to make the case that it's actually pathogenic. The paper also gets into why Larsen's syndrome is genuinely tricky to diagnose in practice: the same variant can look quite different from one patient to the next, and we compared this case against the previously reported Indian patients to sketch out that variability.

Next-generation sequencing has quietly changed how much of chronic kidney disease in children turns out to be monogenic — the estimate this review works from is around 30%, and the number keeps climbing as more genes get tied to more phenotypes. This is a practical review rather than a single case: it walks through when genetic testing actually helps in steroid-resistant nephrotic syndrome, CAKUT, cystic kidney disease, tubulopathies, nephronophthisis, and rarer entries like Fabry disease, Alport syndrome and Lowe syndrome, plus atypical HUS, renal tubular acidosis and nephrolithiasis.

The through-line is that a genetic diagnosis in these conditions isn't just a label — it changes classification, gives a clearer prognosis, can point toward a specific treatment, and feeds directly into genetic and reproductive counselling for the family.