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Sterol C4-methyloxidase-like (SC4MOL) deficiency is an autosomal recessive condition caused by biallelic pathogenic variants in MSMO1, resulting in the accumulation of 4-monomethyl and 4,4′-dimethyl sterols due to an enzymatic block in the cholesterol synthesis pathway. SC4MOL deficiency was first reported in 2011, with only seven additional cases from five unrelated families described in the literature since. Based on these reports, the most characteristic clinical features include the triad of microcephaly, congenital cataracts, and psoriatic dermatitis, followed by delayed growth and puberty, and neurodevelopmental problems. Herein, we describe an 8-year-old boy who presented with congenital cataracts and developmental delay at age 6 months and was found to have biallelic variants in MSMO1 by trio exome sequencing. Initial total methylsterol levels were elevated but responsive to statin therapy, while total cholesterol levels remained normal throughout. Available clinical and biochemical data suggest this individual could represent the mildest case of SC4MOL deficiency to date.

We report three unrelated probands, two male and one female, diagnosed with Aicardi-Goutieres 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.

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.

A female infant is delivered at 38 weeks and 6 days’ gestation, after induction of labor for preeclampsia, to an otherwise healthy 37-year-old, gravida 1, para 0 woman via vacuum-assisted vaginal delivery with 4 pulls and no pop-offs. The vacuum was used secondary to fetal heart rate decelerations. The mother was colonized with group B Streptococcus and received adequate intrapartum antibiotic prophylaxis. The infant is floppy at birth with a weak cry and heart rate greater than 100 beats/min. Continuous positive airway pressure is administered at 5 minutes of age because of respiratory distress, which resolves by 20 minutes of age. The infant’s Apgar scores are 4 and 7 at 1 and 5 minutes, respectively. She has a birthweight of 3.15 kg (43rd percentile). The mother and infant both have O+ blood type and screen negative for antibodies. The infant’s total bilirubin (TB) levels at 25 and 31 hours after birth are 9.1 mg/dL (155.6 μmol/L) and 11.5 mg/dL (196.7 μmol/L), respectively (Fig 1); direct bilirubin is not measured. Triple bank phototherapy (bili blanket and 2 bank overhead bili light) is initiated at 31 hours of age, because of a rapid rise in TB at a rate of 0.4 mg/dL per hour (6.8 μmol/L per hour). (Fig 1) The infant continues to receive phototherapy for 18 hours, with a subsequent TB level of 10.4 mg/dL (177.8 μmol/L). Phototherapy is stopped, and the infant is discharged from the hospital. Figure 1. Total bilirubin by age. Results displayed in conventional units. At 78 hours of age, the infant is readmitted because of a TB level of 18.9 mg/dL (323.2 μmol/L), with a phototherapy TB threshold of 18.3 mg/dL (312.9 μmol/L) and 0.30 mg/dL per hour (5.1 μmol/L per hour) rate of rise (1); direct bilirubin level is 0.63 mg/dL (10.8 μmol/L; normal

Context Sulfate is critical in the biotransformation of multiple compounds via sulfation. These compounds include neurotransmitters, proteoglycans, xenobiotics, and hormones such as dehydroepiandrosterone (DHEA). Sulfation reactions are thought to be rate-limited by endogenous sulfate concentrations. The gene, SLC13A1, encodes the sodium-sulfate cotransporter NaS1, responsible for sulfate (re)absorption in the intestines and kidneys. We previously reported two rare, non-linked, nonsense variants in SLC13A1 (R12X and W48X) associated with hyposulfatemia (P = 9 × 10− 20). Objective To examine the effect of serum sulfate concentration and sulfate-lowering genotype on DHEA homeostasis. Design Retrospective cohort study. Setting Academic research. Patients Participants of the Amish Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study and the Amish Hereditary and Phenotype Intervention (HAPI) Study. Main outcome measures DHEA, DHEA-S, and DHEA-S/DHEA ratio. Results Increased serum sulfate was associated with decreased DHEA-S (P = 0.03) and DHEA-S/DHEA ratio (P = 0.06) in males but not females. Female SLC13A1 nonsense variant carriers, who had lower serum sulfate (P = 9 × 10− 13), exhibited 14% lower DHEA levels (P = 0.01) and 7% higher DHEA-S/DHEA ratios compared to female non-carriers (P = 0.002). Consistent with this finding, female SLC13A1 nonsense variant carriers also had lower total testosterone levels compared to non-carrier females (P = 0.03). Conclusions Our results demonstrate an inverse relationship between serum sulfate, and DHEA-S and DHEA-S/DHEA ratio in men, while also suggesting that the sulfate-lowering variants, SLC13A1 R12X and W48X, decrease DHEA and testosterone levels, and increase DHEA-S/DHEA ratio in women. While paradoxical, these results illustrate the complexity of the mechanisms involved in DHEA homeostasis and warrant additional studies to better understand sulfate's role in hormone physiology.

The phenotype of individuals with glycogen storage disease (GSD) IX appears to be highly variable, even within subtypes. Features include short stature, fasting hypoglycemia with ketosis, hepatomegaly, and transaminitis. GSD IXɑ2 is caused by hemizygous pathogenic variants in PHKA2, and results in deficiency of the phosphorylase kinase enzyme, particularly in the liver. Like other GSDs, GSD IXɑ2 can present with hypoglycemia and post-prandial lactic acidosis, but has never been reported in a newborn, nor with lactic acidosis as the presenting feature. Here we describe the clinical presentation and course of a newborn boy with profound neonatal lactic and metabolic acidosis, renal tubulopathy, and sensorineural hearing loss (SNHL) diagnosed with GSD IXɑ2 through exome sequencing. Review of the literature suggests this case represents an atypical and severe presentation of GSD IXɑ2 and proposes expansion of the phenotype to include neonatal lactic acidosis and renal tubulopathy.

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.

Context Sulfate is critical in the biotransformation of multiple compounds via sulfation. These compounds include neurotransmitters, proteoglycans, xenobiotics, and hormones such as dehydroepiandrosterone (DHEA). Sulfation reactions are thought to be rate-limited by endogenous sulfate concentrations. The gene, SLC13A1, encodes the sodium-sulfate cotransporter NaS1, responsible for sulfate (re)absorption in the intestines and kidneys. We previously reported two rare, non-linked, nonsense variants in SLC13A1 (R12X and W48X) associated with hyposulfatemia (P = 9 × 10− 20). Objective To examine the effect of serum sulfate concentration and sulfate-lowering genotype on DHEA homeostasis. Design Retrospective cohort study. Setting Academic research. Patients Participants of the Amish Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study and the Amish Hereditary and Phenotype Intervention (HAPI) Study. Main outcome measures DHEA, DHEA-S, and DHEA-S/DHEA ratio. Results Increased serum sulfate was associated with decreased DHEA-S (P = 0.03) and DHEA-S/DHEA ratio (P = 0.06) in males but not females. Female SLC13A1 nonsense variant carriers, who had lower serum sulfate (P = 9 × 10− 13), exhibited 14% lower DHEA levels (P = 0.01) and 7% higher DHEA-S/DHEA ratios compared to female non-carriers (P = 0.002). Consistent with this finding, female SLC13A1 nonsense variant carriers also had lower total testosterone levels compared to non-carrier females (P = 0.03). Conclusions Our results demonstrate an inverse relationship between serum sulfate, and DHEA-S and DHEA-S/DHEA ratio in men, while also suggesting that the sulfate-lowering variants, SLC13A1 R12X and W48X, decrease DHEA and testosterone levels, and increase DHEA-S/DHEA ratio in women. While paradoxical, these results illustrate the complexity of the mechanisms involved in DHEA homeostasis and warrant additional studies to better understand sulfate's role in hormone physiology.