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Congenital adrenal hyperplasia

From SNPedia

Congenital adrenal hyperplasia (CAH) are any of several autosomal recessive diseases resulting from mutations of genes for enzymes mediating the biochemical steps of production of cortisol from cholesterol by the adrenal glands (steroidogenesis); several such genes are listed in the table below. Most of these conditions involve excessive or deficient production of sex steroids and can alter development of primary or secondary sex characteristics in some affected infants, children, or adults.[1]

Common medical term % OMIM "'Gene"' Enzyme(s)
21-hydroxylase CAH 90-95% 201910 CYP21A2 P450c21
11β-hydroxylase CAH 5% 202010 CYP11B1 P450c11β
3β-HSD CAH very rare 201810 HSD3B2 3βHSD II
17α-hydroxylase CAH very rare 202110 CYP17A1 P450c17
lipoid CAH
very rare 201710 STAR StAR

23andMe has a high rate of miscalls for SNPs in the CYP21A2 gene. Examples include

This is presumably due to the presence of a nearby CYP21 pseudogene as documented in omim

The most common forms of CAH arise from mutations in the CYP21A2 gene on chromosome 6. This gene encodes steroid 21-hydroxylase, so the corresponding disorder is also commonly known as 21-hydroxylase deficiency. There are at least four recognized clinical forms of congenital adrenal hyperplasia: salt-wasting, simple virilizing (SV) or classic, nonclassic (NC) or late-onset, and cryptic. In some cases a single mutation leads to a single recognized clinical form, but in many cases there are multiple mutations on the same allele, as well as high inter-individual variability.

In terms of prevalence, congenital adrenal hyperplasia is not that rare of a recessive disease type; it is estimated to affect 1/15,000 births, and 1 in 60 individuals are estimated to be (unaffected) carriers of a pathogenic variant.

The following table summarizes the SNPs and their phenotypes; the allele designations are taken from the CYP21A2 Allele table at the Human Cytochrome P450 (CYP) Allele Nomenclature Database. Note that the 'change' indicated is oriented to the forward/plus/cDNA strand, regardless of which strand the dbSNP (or SNPedia) SNP is defined as being on.

Rsid Change Allele name Synonym Clinical type OMIM Clinvar significance GRCh37 position, ch 6 i-id (23andMe) On chip?
rs151344503 G>A CYP21A2*27 Trp406Ter salt-wasting 613815.0022 pathogenic 32008543 i5005427 Ancestry v2c, Ancestry v2d 23andMe v4, 23andMe v3
rs201552310 G>A CYP21A2*171 Gly292Ser salt-wasting 613815.0007 pathogenic 32007917
rs267606756 (- > T) 613815.0033 pathogenic 32007964
rs267606757 A>C CYP21A2*151 Lys121Gln 613815.0035 32006939 Ancestry v2c, Ancestry v2d
rs387906510 delGAGACTAC CYP21A2*10 8bp del salt-wasting 613815.0015 pathogenic 32006910 - 32006917 Ancestry v2, Ancestry v2c, Ancestry v2d
rs397509367 GG>C CYP21A2*25 Arg484Fs classic 613815.0008 pathogenic 32008874 - 32008875
rs6445 C>T CYP21A2*19 Pro453Ser nonclassic 613815.0010 pathogenic 32008783 23andMe v4, Ancestry v2c, Ancestry v2d
rs6467 C>G or A>G CYP21A2*9 613815.0006 pathogenic 32006858 Ancestry v2c, FTDNA2, HumanOmni1Quad, Illumina Human 1M, Ancestry v2d
rs6471 G>C CYP21A2*15 Val281Leu nonclassic 613815.0002 pathogenic 32007887
rs6472 G>C CYP21A2*5 Ser268Thr benign variant 613815.0005 benign 32007849 23andMe v4, 23andMe v3, 23andMe v2
rs6475 T>A CYP21A2*11 Ile172Asn classic 613815.0001 pathogenic 32007203
rs6476 T>A CYP21A2*14 Met239Lys salt-wasting 613815.0016 pathogenic 32007593 Ancestry v2, 23andMe v3, Ancestry v2d
rs7755898 C>T CYP21A2*17 Gln318Ter salt-wasting 613815.0020 Pathogenic 32008198
rs7769409 C>T CYP21A2*18 Arg356Trp classic 613815.0003 32008312 i5005436 23andMe v4, 23andMe v3
rs9378251 C>T CYP21A2*8 Pro30Leu nonclassic 613815.0004 Pathogenic 32006291
rs151344504 G>A CYP21A2*82 Arg426His classic 613815.0026 32008703 i5005431 23andMe v4, 23andMe v3
rs151344505 G>A CYP21A2*71 Val304Met hyperandrogenism 613815.0031 32007956 i5005433 23andMe v4, 23andMe v3
rs151344506 G>A CYP21A2*72 Gly375Ser hyperandrogenism 613815.0032 32008452 i5005434 23andMe v4, 23andMe v3
rs397515532 (- > T) CYP21A2*16 insT; Leu308PheFs Pathogenic 32007960-66
rs72552754 G>A CYP21A2*24 Arg339His nonclassic 613815.0021 Pathogenic 32008262 i5005425 23andMe v4, 23andMe v3
rs72552756 G>C CYP21A2*35 Glu380Asp salt-wasting 613815.0023 32008469
rs72552757 C>T CYP21A2*73 Arg408Cys classic 613815.0030 32008648 i5005432 23andMe v4, 23andMe v3
rs72552758 G>A CYP21A2*55 Gly424Ser classic 613815.0025 32008696 i5005430 23andMe v4, 23andMe v3
rs9378252 A>T CYP21A2*91 His62Leu nonclassic 613815.0034 Pathogenic 32006387 i5005437 23andMe v3 23andMe v4, 23andMe v3