Using genomic applications to glean insights into human biology, we systematically searched for nonsense single nucleotide variants (SNVs) that are rare in the general population but enriched in the Old Order Amish (Amish) due to founder effect. We identified two nonlinked, nonsense SNVs (R12X and W48X) in SLC13A1 (allele frequencies 0.29% and 0.74% in the Amish; enriched 1.2-fold and 3.7-fold, compared to the outbred Caucasian population, respectively). SLC13A1 encodes the apical sodium-sulfate cotransporter (NaS1) responsible for sulfate (re)absorption in the kidneys and intestine. SLC13A1 R12X and W48X were independently associated with a 27.6% (P = 2.7 × 10−8) and 27.3% (P = 6.9 × 10−14) decrease in serum sulfate, respectively (P = 8.8 × 10-20 for carriers of either SLC13A1 nonsense SNV). We further performed the first exome- and genome-wide association study (ExWAS/GWAS) of serum sulfate and identified a missense variant (L348P) in SLC26A1, which encodes the basolateral sulfate-anion transporter (Sat1), that was associated with decreased serum sulfate (P = 4.4 × 10−12). Consistent with sulfate’s role in xenobiotic detoxification and protection against acetaminophen-induced hepatotoxicity, SLC13A1 nonsense SNV carriers had higher aminotransferase levels compared to noncarriers. Furthermore, SLC26A1 L348P was associated with lower whole-body bone mineral density (BMD) and higher serum calcium, consistent with the osteochondrodysplasia exhibited by dogs and sheep with naturally occurring, homozygous, loss-of-function mutations in Slc13a1. This study demonstrates the power and translational potential of systematic identification and characterization of rare, loss-of-function variants and warrants additional studies to better understand the importance of sulfate in human physiology, disease, and drug toxicity.

Purpose of review Human reproduction is remarkably inefficient; with pregnancy loss occurring in 10–30% of clinically recognized pregnancies. Of those, 3–5% of couples experience recurrent pregnancy loss (RPL), more than 50% of who never receive an underlying diagnosis. Herein, we review evidence that genetic changes, including pathogenic variant(s) in highly penetrant genes, may provide an explanation for a proportion of couples with pregnancy loss. Recent findings Genetic abnormalities that may predispose to pregnancy loss include chromosomal aneuploidy, copy number variants, single-gene changes and others. Although previously limited by the need for hypothesis-driven assessment, advancement of various molecular technologies have sheparded in the opportunity to identify molecular cause of highly heterogeneous conditions, including RPL. The identification of causative genetic aberrations associated with RPL demonstrates a promising area of further research. Summary The journey of human development from a single-cell zygote to a term infant is complex process. Early research into copy number variants and highly penetrant single-gene changes may provide diagnosis for a proportion of couples with RPL as well as inform genes critical for early human development.

We report three unrelated probands, two male and one female, diagnosed with Aicardi‐Goutières syndrome (AGS) after screening positive on California newborn screening (CA NBS) for X‐linked adrenoleukodystrophy (X‐ALD) due to elevated C26:0 lysophosphatidylcholine (C26:0‐LPC). Follow‐up evaluation was notable for elevated C26:0, C26:1, and C26:0/C22:0 ratio, and normal red blood cell plasmalogens levels in all three probands. Diagnoses were confirmed by molecular sequencing prior to 12 months of age after clinical evaluation was inconsistent with X‐ALD or suggestive of AGS. For at least one proband, the early diagnosis of AGS enabled candidacy for enrollment into a therapeutic clinical trial. This report demonstrates the importance of including AGS on the differential diagnosis for individuals who screen positive for X‐ALD, particularly infants with abnormal neurological features, as this age of onset would be highly unusual for X‐ALD. While AGS is not included on the Recommended Universal Screening Panel, affected individuals can be identified early through state NBS programs so long as providers are aware of a broader differential that includes AGS. This report is timely, as state NBS algorithms for X‐ALD are actively being established, implemented, and refined.

Although decreased citrulline is used as a newborn screening (NBS) marker to identify proximal urea cycle disorders (UCDs), it is also a feature of some mitochondrial diseases, including MT‐ATP6 mitochondrial disease. Here we describe biochemical and clinical features of 11 children born to eight mothers from seven separate families who were identified with low citrulline by NBS (range 3–5 μM; screening cutoff >5) and ultimately diagnosed with MT‐ATP6 mitochondrial disease. Follow‐up testing revealed a pattern of hypocitrullinemia together with elevated propionyl‐(C3) and 3‐hydroxyisovaleryl‐(C5‐OH) acylcarnitines, and a homoplasmic pathogenic variant in MT‐ATP6 in all cases. Single and multivariate analysis of NBS data from the 11 cases using Collaborative Laboratory Integrated Reports (CLIR; https://clir.mayo.edu) demonstrated citrulline <1st percentile, C3 > 50th percentile, and C5‐OH >90th percentile when compared with reference data, as well as unequivocal separation from proximal UCD cases and false‐positive low citrulline cases using dual scatter plots. Five of the eight mothers were symptomatic at the time of their child(ren)'s diagnosis, and all mothers and maternal grandmothers evaluated molecularly and biochemically had a homoplasmic pathogenic variant in MT‐ATP6, low citrulline, elevated C3, and/or elevated C5‐OH. All molecularly confirmed individuals (n = 17) with either no symptoms (n = 12), migraines (n = 1), or a neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) phenotype (n = 3) were found to have an A or U mitochondrial haplogroup, while one child with infantile‐lethal Leigh syndrome had a B haplogroup.