Whole-exome sequencing (WES) represents a significant breakthrough in clinical genetics, and identifies a genetic etiology in up to 30% of cases of intellectual disability (ID). Using WES, we identified seven unrelated patients with a similar clinical phenotype of severe intellectual disability or neurodevelopmental delay who were all heterozygous for de novo truncating variants in the AT-hook DNA-binding motif-containing protein 1 (AHDC1). The patients were all minimally verbal or nonverbal and had variable neurological problems including spastic quadriplegia, ataxia, nystagmus, seizures, autism, and self-injurious behaviors. Additional common clinical features include dysmorphic facial features and feeding difficulties associated with failure to thrive and short stature. The AHDC1 gene has only one coding exon, and the protein contains conserved regions including AT-hook motifs and a PDZ binding domain. We postulate that all seven variants detected in these patients result in a truncated protein missing critical functional domains, disrupting interactions with other proteins important for brain development. Our study demonstrates that truncating variants in AHDC1 are associated with ID and are primarily associated with a neurodevelopmental phenotype.

Fanconi anemia (FA)-associated severe aplastic anemia (SAA) requires allogeneic hematopoietic cell transplantation (HCT) for cure. With the evolution of conditioning regimens over time, outcomes of alternative donor HCT (AD-HCT) have improved dramatically. We compared outcomes of HLA-matched sibling donor HCT (MSD-HCT; n = 17) and AD-HCT (n = 57) performed for FA-associated SAA at a single institution between 2001 and 2016. Overall survival at 5 years was 94% for MSD-HCT versus 86% for AD-HCT, neutrophil engraftment was 100% versus 95%, platelet recovery was 100% versus 89%, grade II-IV acute graft-versus-host disease (GVHD) was 6% versus 12%, grade III-IV acute GVHD was 6% versus 4%, and chronic GVHD was 0 versus 7%, with no statistically significant differences by type of transplant. The use of UCB was associated with decreased rates of neutrophil recovery in AD-HCT and platelet recovery in both MSD-HCT and AD-HCT. A trend toward a higher serious infection density before day +100 post-HCT was observed in AD-HCT compared with MSD-HCT (P = .02). These data demonstrate that AD-HCT should be considered at the same time as MSD-HCT for patients with FA-associated SAA.

Summary Background Recessive dystrophic epidermolysis bullosa (RDEB) is a severe systemic genodermatosis lacking therapies beyond supportive care for its extensive, life‐limiting manifestations. Objectives To report the safety and preliminary responses of 10 patients with RDEB to bone marrow transplant (BMT) with post‐transplant cyclophosphamide (PTCy BMT) after reduced‐intensity conditioning with infusions of immunomodulatory donor‐derived mesenchymal stromal cells (median follow‐up 16 months). Methods BMT toxicities, donor blood and skin engraftment, skin biopsies, photographic and dynamic assessments of RDEB disease activity were obtained at intervals from pre‐BMT to 1 year post‐BMT. Results Related donors varied from haploidentical (n = 6) to human leucocyte antigen (HLA)‐matched (n = 3), with one HLA‐matched unrelated donor. Transplant complications included graft failure (n = 3; two pursued a second PTCy BMT), veno‐occlusive disease (n = 2), posterior reversible encephalopathy (n = 1) and chronic graft‐versus‐host disease (n = 1; this patient died). In the nine ultimately engrafted patients, median donor chimerism at 180 days after transplant was 100% in peripheral blood and 27% in skin. Skin biopsies showed stable (n = 7) to improved (n = 2) type VII collagen protein expression by immunofluorescence and gain of anchoring fibril components (n = 3) by transmission electron microscopy. Early signs of clinical response include trends toward reduced body surface area of blisters/erosions from a median of 49·5% to 27·5% at 100 days after BMT (P = 0·05), with parental measures indicating stable quality of life. Conclusions PTCy BMT in RDEB provides a means of attaining immunotolerance for future donor‐derived cellular grafts (ClinicalTrials.gov identifier NCT02582775). What's already known about this topic? Severe, generalized recessive dystrophic epidermolysis bullosa (RDEB) is marked by great morbidity and early death. No cure currently exists for RDEB. Bone marrow transplant (BMT) is the only described systemic therapy for RDEB. What does this study add? The first description of post‐transplant cyclophosphamide (PTCy) BMT for RDEB. PTCy was well tolerated and provided excellent graft‐versus‐host disease prophylaxis, replacing long courses of calcineurin inhibitors in patients receiving human leucocyte antigen‐matched sibling BMT. What is the translational message? The PTCy BMT platform permits identification of a suitable related donor for most patients and for subsequent adoptive transfer of donor nonhaematopoietic cells after establishment of immunological tolerance.

DK provided samples and clinical information. TW assisted with animal studies. OF performed PacBio sequencing. SS, MB, and KB performed single cell and Visium sequencing. TS provided pathology expertise. RV provided biostatistical expertise. AS and PC supervised the study. AS and SC obtained funding. AW and AS wrote the manuscript with input from other authors.Competing interests: Rocket Pharmaceuticals provided research funding and partial salary support to A.S. for an unrelated project. P.J.C. is a founder, director and consultant for Mu Genomics Ltd. B.S. is a co-inventor of intellectual property related to DCN1 small molecule inhibitors licensed by MSK to Cinsanso. He has rights to receive royalty income as a result of this arrangement. MSK has financial interests related to this intellectual property and Cinsanso as a result of this arrangement. Other authors declare no competing interests.