A recurrent de novo germline variant in the MAX gene, p.(Arg60Gln), has recently been associated with polydactyly-macrocephaly syndrome in six unrelated individuals. Affected individuals presented with progressive macrocephaly, post-axial polydactyly, developmental delay, autistic features and a series of craniofacial, brain, cardiac, ocular, and renal anomalies. Here, we describe two unrelated female probands with the known recurrent MAX variant, c.179G>A p.(Arg60Gln), who presented with the emerging phenotypes of the MAX-associated syndrome. We also propose that genitourinary abnormalities, including Mayer-Rokitanski-Kuster-Hauser syndrome in one individual, may constitute an expansion of the known phenotype. These findings contribute to the current knowledge regarding the phenotypic spectrum of MAX-associated polydactyly-macrocephaly syndrome.

Genome sequencing (GS) has emerged as the gold standard for diagnosing patients with rare diseases. As with many emerging technologies, equitable access remains a concern. To evaluate the feasibility and diagnostic impact of expanding access to GS, we report our experience implementing CincyKidsSeq, a prospective study offering GS as a "proband-first" test. Participants of all ages with at least one symptom were referred by genetics or non-genetics healthcare providers, or alternatively, were self-referred from February 2024 to February 2025. This diverse referral structure was evaluated for diagnostic yield while maintaining clinical oversight through a hybrid model in which reportable variants are delivered through genetic providers. The overall diagnostic yield of GS on 313 participants was 22% in the unstratified cohort. Self-referred patients had a higher diagnostic yield (11/33; 33%), compared with patients referred by a non-genetics provider (27/98; 27%), or genetics provider (32/182; 18%). Self-referred individuals were older, more likely to be female, frequently test-naïve, and utilized fewer human phenotype ontology (HPO) terms (p value = 0.0016). Self-referral may serve as an effective and complementary pathway for improving access to GS. Empowering families to initiate GS may be a reasonable pathway for an alternative model for genetic service delivery.

A homozygous LZTR1 frameshift variant resulting from maternal uniparental disomy of chromosome 22 [UPD(22)] is associated with bone marrow failure and dysmorphic features distinct from those of Noonan syndrome. Biallelic LZTR1 variants lacking the second BTB domain may underlie a rare clinical phenotype characterized by bone marrow failure.

Huntington's disease (HD) has prevalent, life-altering consequences for affected individuals, relatives, familial caregivers and systemic functioning. However, the shared psychosocial impacts of HD across family systems are inadequately understood, and a synthesis of evidence regarding these experiences is currently lacking. This thematic synthesis provides an up-to-date integration of qualitative research describing psychological, social and relational difficulties experienced by HD families. A systematic search across PsycINFO, CINAHL, MEDLINE and Scopus identified nine qualitative studies. Four interconnected superordinate themes were developed, describing a disintegration of HD families from society, HD-related emotional and psychological burdens, an interplay of extrinsic stressors and recalibration of the family system. These findings extend existing knowledge about systemic impacts of HD, highlighting diverse and pervasive psychological and social difficulties faced by families. The synthesis recommends the development of interventions and clinical understandings to appropriately support family systems around psychosocial and relationship dynamic challenges in the unique context of HD.

Whole-genome sequencing identifies intronic variants whose pathogenicity can be predicted with tools like SpliceAI. However, an actionable classification of such variants may require RNA-based validation, which can be limited by low expression in clinically accessible tissues. We report two fetuses from one family with Arthrogryposis multiplex congenita 6 (AMC6 [OMIM # 619334]) and biallelic NEB variants: a paternally inherited likely pathogenic frameshift variant, Chr2(GRCh38):g.151579391del; NM_001164508.2:c.16653del; NP_001157980.2:p.(Asp5552ThrfsTer5), and a maternally inherited intronic variant of uncertain clinical significance, Chr2(GRCh38):g.151496267G>A; NM_001164508.2:c.24486+9C>T; NP_001157980.2:p.(?). Because NEB is poorly expressed in fibroblasts, we used CRISPR activation to induce its expression in fibroblasts from the heterozygous mother. RNA-sequencing subsequently confirmed that the intronic variant generated a novel splice donor site associated with inferred loss of splicing at the canonical donor site. After NMD-inhibition, we could thus identify 45.5% of NEB transcripts with a 7 bp exon extension, predicted to result in a protein-coding frameshift. The intronic variant was classified as likely pathogenic, allowing a genetic diagnosis.

Biallelic pathogenic expansions in RFC1 contribute to the genetic etiology of PD, with a frequency similar to that of other known autosomal recessive PD genes. RFC1-positive PD is currently not clinically distinguishable from RFC1-negative PD, but genetic background may play a role in future therapies or other interventions.

Chromatinopathies (CPs) are an expanding group of rare genetic disorders affecting epigenetic machinery. Besides an intricate genotypic spectrum, these conditions share overlapping phenotypes characterized by neurocognitive impairment, growth defects and distinctive, but often convergent, facial features. Although individually rare, the landscape of CPs is increasingly growing and represents an emerging and possibly underestimated cause of disability. Due to their complexity and rarity, accurate diagnosis and management pose significant difficulties. To address these challenges and gain a deeper overview of these diseases' spectrum, we retrospectively collected clinical characteristics of 239 patients diagnosed with CPs and critically analyzed their diagnostic journey, growth charts, neurological and gestaltic features. Starting from the largest collection of CPs to date, our data point to wide sequencing analyses as the best shortcut to diagnosis. We have also demonstrated the importance of growth defects in this group of disorders that require dedicated growth tables, and we have delved into the great variability of neurological and clinical burden in these conditions. This retrospective study provides a significant advance in our understanding of these rare diseases and will help to improve diagnostic, therapeutic, and clinical approaches to CPs and to develop personalized multidisciplinary care plans for affected patients.

Mitochondrial DNA depletion syndrome 1 (MTDPS1) is a rare autosomal recessive disorder caused by mutations in the TYMP gene, leading to mitochondrial failure. Hallmark features include gastrointestinal dysmotility, cachexia, peripheral neuropathy, ocular signs, hearing loss, and leukoencephalopathy. We present a 39-year-old woman with premature ovarian insufficiency (POI) as a novel endocrine manifestation of MTDPS1. She had normal pubertal development with menarche at age 10. In her mid-20s, she developed fatigue, nausea, vomiting, abdominal pain, weight loss, and amenorrhoea at age 29. Investigations revealed POI with elevated FSH levels, a normal karyotype, negative autoimmune markers. Imaging showed a thin endometrium, small ovaries, osteoporosis, severe gastroparesis. An incidental renal angiomyolipoma prompted an MRI of the brain, revealing symmetrical abnormal white matter changes, suggestive of leukodystrophy. Given diagnostic uncertainty and a history of consanguinity she was referred to clinical genetics and underwent whole genome sequencing which identified a novel homozygous variant (c.559C > T; p.(Gln 187*)) in the TYMP gene, confirming MTDPS1. Though POI is not a well-established feature of MTDPS1, mutations in other genes linked with mitochondrial function are known to be associated with POI and we postulate that this is an endocrine manifestation of MTDPS1. Genetic assessment should be considered in unexplained POI, particularly if associated with other clinical features/consanguinity.