Konishi A, Tachibana M, Oto Y
… +8 more, Kashimada K, Ishii T, Aoki Y, Muroya K, Takahashi Y, Kurosawa K, Ogata T, Kawai M
Am J Med Genet A
· 2026 May · PMID 42219582
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Prader-Willi syndrome (PWS) is a rare neurogenetic disorder characterized by endocrine, metabolic, behavioral, and psychiatric features. These manifestations may affect health-related quality of life (HRQOL). Evidence on...Prader-Willi syndrome (PWS) is a rare neurogenetic disorder characterized by endocrine, metabolic, behavioral, and psychiatric features. These manifestations may affect health-related quality of life (HRQOL). Evidence on HRQOL in adolescents and adults with PWS remains limited. This study evaluated HRQOL and examined sex, age, genetic, and behavioral factors associated with HRQOL in individuals with genetically confirmed PWS aged 16 years and over. A proxy-reported questionnaire survey was conducted through a Japanese national PWS support group, and responses from 119 participants (median age, 25 years) were analyzed. The primary outcome was a EuroQol five-dimension five-level (EQ-5D-5L) index value in the upper tertile of the study distribution (≥ 0.744). The median EQ-5D-5L index value was 0.665 (IQR, 0.549-0.775), and the mean was 0.652 (SD, 0.180). Only 4.3% of participants reported no problems in any dimension. Younger age (16-19 years) (OR, 4.62; 95% CI, 1.42-15.1), the deletion genetic subtype (4.79; 1.15-20.0), and lower problematic food-related behaviors (0.90; 0.83-0.97) were independently associated with an EQ-5D-5L index value in the upper tertile. Support during the transition from late adolescence to early adulthood and attention to problematic food-related behaviors may be important for improving the HRQOL of individuals with PWS.
Am J Med Genet A
· 2026 May · PMID 42215316
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RASA1-related disorders typically present as capillary malformation-arteriovenous malformation (CM-AVM) syndrome; visceral, especially diffuse gastrointestinal (GI) involvement has not previously been reported. We descri...RASA1-related disorders typically present as capillary malformation-arteriovenous malformation (CM-AVM) syndrome; visceral, especially diffuse gastrointestinal (GI) involvement has not previously been reported. We describe the first case of extensive GI vascular malformations caused by a novel RASA1 splice-site mutation. A 29-year-old man presented with 2-year intermittent hematochezia. Contrast-enhanced CT, double-balloon enteroscopy (DBE) and superior mesenteric angiography revealed diffuse vascular malformations throughout the small bowel and stomach. Targeted next-generation sequencing identified a heterozygous de-novo splice-donor mutation (NM_002890.3:c.1049+2T>G) in intron 6 of RASA1, predicted to be pathogenic. An incidental likely-pathogenic heterozygous frameshift variant in MYBPC3 (NM_000256.3:c.989del, p.Pro330HisfsTer20) was also detected. ISSVA (International Society for the Study of Vascular Anomalies) classifies it as Capillary Malformation-Arteriovenous Malformation (CM-AVM) within Fast-flow Vascular Malformations. Multidisciplinary consultation concluded that the lesions were too extensive for curative resection; the patient was discharged for close surveillance with a plan for sirolimus trial and selective surgical, Interventional or endoscopic hemostasis as needed. This case expands the phenotypic spectrum of RASA1 loss-of-function variants to include diffuse GI vascular malformations. When young patients present with obscure GI bleeding and imaging suggests multifocal angiodysplasia, germline RASA1 analysis should be considered. Early molecular diagnosis facilitates family counseling, targeted surveillance, and personalized therapy.
Kostoulas C, Sesse A, Bouba I
… +4 more, Najdecki R, Konitsiotis S, Markoula S, Georgiou I
Am J Med Genet A
· 2026 May · PMID 42212615
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Carrier screening is a long-standing genetic testing process offered to at-risk couples, with or without a family history, who might have pregnancies affected by an autosomal recessive (AR) or X-linked (XL) disorder. A t...Carrier screening is a long-standing genetic testing process offered to at-risk couples, with or without a family history, who might have pregnancies affected by an autosomal recessive (AR) or X-linked (XL) disorder. A total of 276 unrelated individuals, initially referred for rare disorder screening by clinicians, were enrolled in this study and tested by Exome sequencing (ES). Expanded carrier screening (ECS) was performed for 176 disorders that met the inclusion criteria of the ACMG and ACOG. Genes with single nucleotide variants (SNVs) identified with a carrier rate > 1% for AR disorders included HBB, CFTR, PMM2, NPHS2, GJB2, ACADM, ALDOB, MEFV, MKS1, NEB, PAH, ATM, CPT2, CYP21A2, AGXT, BBS1, CAPN3, COL4A4, DHCR7, GAA, IVD, LAMA2, SLC22A5, SLC26A4, USH2A. For XL disorders, variants were detected in the RS1 gene. ECS offers a wealth of information about SNVs related to AR and XL disorders in specified populations. The information obtained from ECS provides multiple advantages: (a) it identifies the most prominent risks in health care in a given population and contributes to the prevention of genetic disorders, (b) it enriches available databases with pathogenic or likely pathogenic SNVs, and (c) it records novel targets for molecular clinical genetic testing.
Johnston K, Nagamani SCS, Miller BS
… +4 more, Rauen KA, Boyce RD, Musaad S, Magoulas PL
Am J Med Genet A
· 2026 May · PMID 42210490
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Cardio-facio-cutaneous (CFC) syndrome is a rare, multiple congenital anomaly disorder in which individuals commonly experience faltering growth; however, systematic analysis of growth parameters in this disorder has not...Cardio-facio-cutaneous (CFC) syndrome is a rare, multiple congenital anomaly disorder in which individuals commonly experience faltering growth; however, systematic analysis of growth parameters in this disorder has not been performed. We recruited 69 participants with CFC through CFC International and collected data on assessing height, weight, and body mass index (BMI). We found that the height-for-age and weight-for-age Z-scores were consistently lower in individuals with CFC than in the reference population and that children with CFC experience growth restriction from infancy to adulthood. Our findings show that as individuals age, their height Z-scores remain constant (-2 to -3 SD). However, over time, their weight shows a progressive decrease from average. There were no significant differences between the mean Z-scores of the growth parameters based on an individual's history of enteral feeding, gene associated with diagnosis, nor growth hormone deficiency status. This implies that feeding modality and severity of feeding difficulties may not be directly related to growth. Other factors could be responsible, such as malabsorption of nutrients, constitutional growth delay, hormonal deficiencies or resistance, or cardiac abnormalities. Our study is one of the first to systematically characterize growth parameters and analyze the association of clinical covariates with these parameters in individuals with CFC syndrome. Accurate assessment of growth in this rare condition will allow providers to recognize outliers of growth in their patients with CFC when compared to other individuals with CFC and make necessary referrals and recommendations, which may ultimately improve outcomes.
Bai Y, Xu J, Xin J
… +3 more, Mo W, Huang M, Tang C
Am J Med Genet A
· 2026 May · PMID 42200300
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Adams-Oliver syndrome (AOS) is characterized by scalp aplasia cutis congenita (ACC) and terminal transverse limb defects (TTLD). Autosomal recessive AOS type 2 caused by DOCK6 variants is usually accompanied by central-n...Adams-Oliver syndrome (AOS) is characterized by scalp aplasia cutis congenita (ACC) and terminal transverse limb defects (TTLD). Autosomal recessive AOS type 2 caused by DOCK6 variants is usually accompanied by central-nervous-system and ocular anomalies. We report two unrelated children who each carried compound heterozygous DOCK6 variants. Both presented with variable degrees of global developmental delay and visual impairment, but neither showed ACC or TTLD. Our observations highlight the phenotypic variability in DOCK6-related AOS and a possible ascertainment bias in screening patients only with typical AOS phenotypes. Genome sequencing and related genetic testing techniques are advised.
DiFalco CR, Williams A, Soler-Alfonso C
… +4 more, Waskow E, Mizerik E, Scaglia F, Murali CN
Am J Med Genet A
· 2026 May · PMID 42192213
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Multiple mitochondrial dysfunctions syndrome 1 (MMDS1, MIM #605711) due to NFU1 gene defects is an ultra-rare autosomal recessive inborn error of metabolism associated with reduced function of NFU1 iron-sulfur cluster (I...Multiple mitochondrial dysfunctions syndrome 1 (MMDS1, MIM #605711) due to NFU1 gene defects is an ultra-rare autosomal recessive inborn error of metabolism associated with reduced function of NFU1 iron-sulfur cluster (ISC) scaffold protein. This disorder demonstrates variable clinical features including hypotonia, epileptic encephalopathy, respiratory failure, lactic acidosis, hyperglycinemia, and hemodynamic instability. One unique feature of this mitochondrial disorder is the common manifestation of pulmonary arterial hypertension (PAH), for which the pathophysiologic mechanism is not well defined to date. Here, we report a case of infantile-onset lactic acidosis, refractory epilepsy with encephalopathy, hyperglycinemia, and severe PAH in a patient who underwent rapid genome sequencing (GS) which identified compound heterozygous variants in NFU1 consistent with a diagnosis of MMDS1. We additionally review the literature on published cases of MMDS1 including developments in the understanding of the intracellular impact of defective ISC proteins. Recent studies delineate a multifactorial pathogenesis including globally dysregulated energy metabolism, specific deficiencies in oxidative phosphorylation, and excess reactive oxygen species (ROS) production. A key difference between established animal models of this disorder and human cases published to date is that the previously described sex-based phenotype discrepancy in rats was not recapitulated in this review. Identification of the clinical combination of lactic acidosis, PAH, and hyperglycinemia during diagnostic evaluation should raise suspicion for a defect of the ISC pathway, and further investigations of the cellular pathophysiology of this disorder may provide insight into the phenotypic spectrum of human disease and potential therapeutic targets.
Am J Med Genet A
· 2026 May · PMID 42186860
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Achondroplasia (OMIM #100800), the most common skeletal dysplasia, results from the recurrent FGFR3 c.1138G > A (p.Gly380Arg) gain-of-function variant, which constitutively activates fibroblast growth factor receptor 3 s...Achondroplasia (OMIM #100800), the most common skeletal dysplasia, results from the recurrent FGFR3 c.1138G > A (p.Gly380Arg) gain-of-function variant, which constitutively activates fibroblast growth factor receptor 3 signaling and impairs endochondral ossification. The 16p11.2 microdeletion (OMIM #611913) is a recurrent ~600 kb copy-number variant associated with developmental delay, autism spectrum disorder, epilepsy, and obesity, encompassing dosage-sensitive genes including MAPK3, KCTD13, and PRRT2. Recent genome-wide analyses have linked 16p11.2 deletion to a 13.9-fold increased risk of neuroblastoma, though no association with medulloblastoma has been documented. Medulloblastoma, the most common malignant pediatric brain tumor, is classified into molecularly defined subgroups-WNT-activated, SHH-activated, Group 3, and Group 4-each with distinct genetic drivers and clinical outcomes. We describe a 13-year-old male with achondroplasia confirmed by the pathogenic FGFR3 c.1138G > A variant and a de novo 16p11.2 microdeletion who developed metastatic non-WNT/non-SHH (Group 4) medulloblastoma with leptomeningeal dissemination (M3) at age 12. Despite multimodal therapy including resection, craniospinal irradiation, and combination chemotherapy, the tumor recurred and progressed. The patient died at age 13. To our knowledge, this is the first report of co-occurring achondroplasia and 16p11.2 deletion complicated by medulloblastoma. Although neither condition independently confers established risk for this tumor, both perturb MAPK/ERK signaling-a pathway implicated in Group 4 medulloblastoma biology. This case underscores the importance of recognizing multilocus pathogenic variation and supports further investigation of potential interactions between developmental and oncogenic signaling networks.
Bland EM, Weinstein AN, Kao EC
… +2 more, Zhao X, Weisz-Hubshman M
Am J Med Genet A
· 2026 May · PMID 42178607
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Autosomal dominant PPP1R12A-related genitourinary and/or brain malformation syndrome is a recently described multisystem disorder caused by loss-of-function variants in the protein phosphatase 1 regulatory subunit 12a (P...Autosomal dominant PPP1R12A-related genitourinary and/or brain malformation syndrome is a recently described multisystem disorder caused by loss-of-function variants in the protein phosphatase 1 regulatory subunit 12a (PPP1R12A) gene. To date, 22 affected individuals have been reported with variable brain malformations and genitourinary anomalies, including differences of sexual development. Of these cases, four probands had anomalies involving both organ systems. Here, we report a 12-year-old individual with global developmental delay, semi-lobar holoprosencephaly, microcephaly, spastic quadriplegia, bilateral polydactyly, and ambiguous genitalia. The proband was found to have a 46,XY chromosome complement. Trio genome sequencing with sequential RNA sequencing revealed a novel intronic variant that generates an out-of-frame transcript with a premature stop codon, supporting a loss-of-function mechanism. We review previously reported cases of PPP1R12A-related disease and summarize genotypes and frequency of reported clinical features, further illustrating the variable expressivity associated with this condition. Our findings broaden the phenotypic and genotypic spectrum of PPP1R12A and reinforce the role of transcript-level analysis in the evaluation of suspected splicing variants.
Blanc A, Nemos C, Bonnet C
… +5 more, Renaud M, Chapuis S, Boiroux P, Babinet MN, Demily C
Am J Med Genet A
· 2026 May · PMID 42178606
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Smith-Magenis syndrome (SMS) results from either a recurrent 17p11.2 deletion or pathogenic variants in the retinoic acid induced 1 gene (RAI1). While neurodevelopmental impairment and behavioral dysregulation are well r...Smith-Magenis syndrome (SMS) results from either a recurrent 17p11.2 deletion or pathogenic variants in the retinoic acid induced 1 gene (RAI1). While neurodevelopmental impairment and behavioral dysregulation are well recognized, systematic genotype-stratified analyses across psychiatric domains remain limited. We conducted a retrospective genotype-stratified study of 52 individuals with molecularly confirmed SMS (43 with 17p11.2 deletions; 9 with pathogenic RAI1 variants) evaluated at the French national coordinating Reference Center for Rare Diseases specializing in psychiatric manifestations (CRMR GénoPsy, Lyon, France). Standardized neurodevelopmental and psychiatric data were extracted and compared using Fisher's exact tests. Intellectual disability was observed in 37/43 deletion carriers (86.0%) and in none of the individuals with RAI1 variants (0/9; OR = 109.6, 95% CI [5.66-2122.3], p = 1.3 × 10). Extended deletions were associated with maximal severity. Deletion carriers also exhibited prominent externalizing dysregulation, including self-injurious behavior (34/43 vs. 5/9) and hetero-aggressiveness (28/43 vs. 4/9). Dystonia was observed in 5/43 deletion carriers (11.6%), including 2/2 individuals with extended deletions, and in 0/9 individuals with RAI1 variants (p = 0.573; OR = 3.09; 95% CI [0.16-60.6]; Haldane correction). In contrast, RAI1 variants demonstrated relative cognitive preservation, with some individuals achieving normal-range IQ, but showed increased internalizing vulnerability, including anxiety (5/9 [55.6%] vs. 5/43 [11.6%]; OR = 0.11, 95% CI [0.02-0.53], p = 0.008) and social withdrawal (4/9 [44.4%] vs. 4/43 [9.3%]; OR = 0.13, 95% CI [0.02-0.68], p = 0.023). Across genotypes, ADHD and sleep-circadian disturbances were highly prevalent. This study refines genotype-phenotype correlations in SMS by delineating two partially divergent neuropsychiatric trajectories. 17p11.2 deletions are associated with pronounced developmental burden and externalizing dysregulation, whereas RAI1 variants are characterized by relatively preserved cognition and heightened internalizing vulnerability. Shared ADHD and sleep-circadian disturbances highlight cross-genotypic targets for genotype-informed clinical management.
Am J Med Genet A
· 2026 May · PMID 42178603
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Stüve-Wiedemann Syndrome (SWS) is a rare autosomal recessive skeletal dysplasia caused by variations in the leukemia inhibitory factor receptor (LIFR) gene. Due to its high rate of mortality in early life, current litera...Stüve-Wiedemann Syndrome (SWS) is a rare autosomal recessive skeletal dysplasia caused by variations in the leukemia inhibitory factor receptor (LIFR) gene. Due to its high rate of mortality in early life, current literature is largely limited to children with SWS. We present a case report of a 35-year-old female with SWS, one of the few documented adults with SWS. She was diagnosed at age 34 after clinical exome sequencing identified homozygous pathogenic variants in LIFR at c.756dup (p.Lys253*), a known pathogenic variant associated with SWS. Her past medical history consists of feeding and respiratory difficulties in infancy, recurrent fractures, a deep vein thrombosis of the upper extremity, osteoporosis, and an incidental finding of a brain aneurysm. Of note, she has undergone over 25 surgeries without complications from anesthesia. As an adult, her symptoms include heart palpitations, fatigue, restless leg syndrome, temperature dysregulation, poor dentition, and bone fragility. On physical exam, she displays short stature, blue sclera, kyphoscoliosis, significant loss of range of motion in multiple joints, and fusions in the fingers and toes. To our knowledge, she is the oldest reported individual in the literature with SWS, and her case provides insight into how symptoms evolve over time.
Pomeroy JJ, Richards J, Sweeney BR
… +14 more, Kumar S, Queen KE, Zaritsky J, Cramer CH, Traboulsi EI, Scruggs BA, Davis EE, Keifer E, McGibbon E, Ogden T, De Graaf B, Hymers T, Forsythe E, Beales P
Am J Med Genet A
· 2026 May · PMID 42175648
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Considerable advances have been made in our understanding of Bardet-Biedl syndrome (BBS), particularly in its core clinical features and molecular genetics, warranting an update to the existing diagnostic criteria framew...Considerable advances have been made in our understanding of Bardet-Biedl syndrome (BBS), particularly in its core clinical features and molecular genetics, warranting an update to the existing diagnostic criteria framework. Using a rigorous, evidence-based, and consensus-driven process, a multidisciplinary group of international experts and patient-led organizations developed an updated diagnostic algorithm. This algorithm provides practical, updated guidance for clinicians, including a pathway for accurately incorporating genetic findings into the diagnostic process. We recommend that a clinical diagnosis requires either 4 major criteria or 3 major and 2 minor criteria. Revised major criteria are retinal dystrophy, obesity (or overweight in individuals < 2 years old), congenital anomalies of the kidney and urinary tract or chronic kidney disease, hypogonadism/genital anomalies, neurodevelopmental/neurocognitive manifestations, and postaxial polydactyly. The diagnosis can also be established with a positive genetic testing result in patients exhibiting ≥ 1 major criterion, provided that genetic findings should be interpreted in the context of the patient's clinical presentation, age, family history, and overlap with related ciliopathies. These consensus criteria offer a simple algorithm incorporating updated definitions for major and minor criteria and genetic testing to support a timely and accurate diagnosis of patients with BBS, inform genetic counseling, and potentially facilitate earlier access to treatment. Trial Registration: CRIBBS Registry; ClinicalTrials.gov: NCT02329210.
Yokoyama-Rebollar E, Villarroel CE, Barragán-Arévalo T
… +5 more, Chacón-Camacho OF, Orozco-Ávila DC, Leal-Anaya P, Del Castillo-Ruiz V, Zenteno JC
Am J Med Genet A
· 2026 May · PMID 42170786
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GZF1-related phenotype (GZF1RP) has been referred to by different names, including autosomal recessive Larsen syndrome (LRS) and "joint laxity, short stature, and myopia". Only ten patients from five families have been r...GZF1-related phenotype (GZF1RP) has been referred to by different names, including autosomal recessive Larsen syndrome (LRS) and "joint laxity, short stature, and myopia". Only ten patients from five families have been reported, all of whom carry biallelic variants of GZF1. They share short stature and joint dislocation with LRS; however, they present with severe ocular manifestations, suggesting that GZF1RP may be specific. In this study, we described three new patients with severe ophthalmologic phenotypes, including congenital glaucoma and abnormal iris morphology. We identified the GZF1: c.1440del (p.His481IlefsTer26) variant in homozygosity in two affected sisters and compound heterozygosity in the third patient: the same c.1440del plus c.1451_1452del (p.Cys484fs). In addition to expanding the molecular spectrum, we identified new radiological findings, such as cervical segmentation defects, carpal shortening, and lower lumbar sacralization, as well as some clinical findings uncommon in previous cases, such as umbilical hernia and congenital heart disease. We also searched for LRS case series with pathogenic variants in FLNB to identify differences between the two entities. The comparison allows us to define a recognizable GZF1RP that includes severe ocular defects, short stature, facial dysmorphism, joint hypermobility/dislocations, scoliosis, thoracic deformity, progressive hearing loss, umbilical hernia, and hypodontia.
Siu VM, Kenana R, Chakrabarti R
… +21 more, Wilhelm SDP, Andrews J, Leat SJ, Parker C, Miller M, Nangle LA, McCaul W, Chowdhury A, Hutchings N, Adams RA, Guy L, Rhody M, Juncal V, Mendes MI, Smith DEC, Salomons GS, Moresco AA, McCulloch DL, Morton DH, Heinemann IU, Rupar CA
Am J Med Genet A
· 2026 May · PMID 42157369
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Autosomal recessive HARS1-related disorder (originally described as Usher syndrome type 3B) caused by a homozygous Y454S variant in the histidyl-tRNA synthetase gene (HARS1) is characterized by progressive sensorineural...Autosomal recessive HARS1-related disorder (originally described as Usher syndrome type 3B) caused by a homozygous Y454S variant in the histidyl-tRNA synthetase gene (HARS1) is characterized by progressive sensorineural hearing and vision loss and respiratory deterioration with risk for sudden death following febrile illnesses. In-vitro studies have previously shown that histidine can rescue a humanized yeast model for pathogenic HARS alleles. Fourteen children homozygous for HARS Y454S were treated with supplemental oral histidine (50 mg/kg BID) and monitored with bloodwork and physical, visual, and audiometry assessments during a 3-year clinical trial, then followed for more than 4 years on histidine in the post-trial period. Patient fibroblasts were assessed for response to histidine. Hearing and vision remained stable, and growth improved significantly. Children remained healthy, with no severe deteriorations despite exposure to bacterial and viral infections, including COVID-19. Gains in growth were maintained in the post-trial period on varying levels of histidine supplementation. Daily oral histidine supplementation in children with autosomal recessive HARS1-related disorder can ameliorate or slow the progression of disease and is safe, inexpensive, and well tolerated. This study adds to the growing list of autosomal recessive ARSopathies (aminoacyl-tRNA synthetase disorders) that are amenable to amino acid supplementation.
Rustad CF, von der Lippe C, Nordgarden H
… +4 more, Miller JU, Weedon-Fekjær MS, Bragadottir R, Sigurdardottir S
Am J Med Genet A
· 2026 May · PMID 42157030
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Bardet-Biedl syndrome (BBS) is a rare genetic condition with a broad phenotypic spectrum. Knowledge about quality of life, executive functioning, and eating behavior in adults with BBS remains limited. This study aimed t...Bardet-Biedl syndrome (BBS) is a rare genetic condition with a broad phenotypic spectrum. Knowledge about quality of life, executive functioning, and eating behavior in adults with BBS remains limited. This study aimed to assess health-related quality of life (HRQoL), everyday executive functioning, and eating behavior in adults with BBS and examine associations among these domains. Thirty adults with BBS (50% male, aged 20-69 years) participated in a cross-sectional study. HRQoL was measured using the Short Form Health Survey (SF-36), everyday executive functioning with the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A), and eating behavior with the Three-Factor Eating Questionnaire (TFEQ-R21). Compared with the general population, adults with BBS scored significantly lower on the Physical Functioning, General Health, and Social Function subscales of the SF-36, and 17% of participants fell within the clinically impaired range on the Physical Component Summary. While median BRIEF-A T-scores on subscales were within normative ranges, 7%-13% of participants exhibited BRIEF-A indices scores in the clinically impaired ranges, all of whom had recent depression and reported significant poorer executive difficulties. On the TFEQ-R21, the average cognitive restraint scale showed the highest score. Adults with BBS reported reduced HRQoL in the domains of physical functioning, general health, and social function compared to the general population. Additionally, a small subgroup with recent depression appeared to account for the observed everyday executive difficulties, suggesting that these may be concentrated in those with comorbid depression. This emphasizes the need for multidisciplinary follow-up of individuals with BBS, including focus on everyday executive functioning and eating behavior in addition to medical and psychosocial care. Trial Registration: ClinicalTrials.gov: NCT05400278.
Am J Med Genet A
· 2026 May · PMID 42153583
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Cenani-Lenz syndactyly syndrome (CLSS, OMIM 212780) is a rare autosomal recessive disorder characterized by syndactyly and oligodactyly of the digits, fusion of carpal and tarsal bones, and radioulnar synostosis. Craniof...Cenani-Lenz syndactyly syndrome (CLSS, OMIM 212780) is a rare autosomal recessive disorder characterized by syndactyly and oligodactyly of the digits, fusion of carpal and tarsal bones, and radioulnar synostosis. Craniofacial anomalies and renal malformations have been reported in approximately half of cases, with variable expression. The condition results from homozygous or compound heterozygous mutations in the LRP4 gene. We identified a consanguineous family with four individuals affected by CLSS, comprising two brothers and their two maternal male cousins. All patients presented with bilateral complex syndactyly, characterized by absent phalanges, reduced and disorganized metacarpals, and cutaneous toe syndactyly. The 2-year-old proband had a horseshoe kidney, whereas his 6-year-old cousin presented with right renal agenesis. None of the patients exhibited growth and developmental delay, cardiac anomalies, or intellectual disability. Based on the clinical suspicion of CLSS, targeted next-generation sequencing of the LRP4 gene was performed. This analysis revealed a biallelic variant, c.3830G>T (NM_002334.3), resulting in the protein change p.Arg1277Leu, which has not been previously described. CLSS is a rare congenital disorder affecting distal limb development and is frequently associated with renal malformations and variable dysmorphic features. In this report, we describe four affected individuals carrying a novel homozygous missense variant in the LRP4 gene, thereby broadening the clinical and genetic spectrum of CLSS and highlighting the pathogenic significance of this newly identified variant.
Am J Med Genet A
· 2026 May · PMID 42144698
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In patients with Smith-Magenis syndrome (SMS), an inverted circadian rhythm of melatonin (MT) contributes to the sleep disturbance. Standard treatment of sleep disturbance with MT often leads to extremely high daytime MT...In patients with Smith-Magenis syndrome (SMS), an inverted circadian rhythm of melatonin (MT) contributes to the sleep disturbance. Standard treatment of sleep disturbance with MT often leads to extremely high daytime MT levels, resulting in even more sleep disorders. We therefore retrospectively evaluated the MT data of 89 SMS patients. Mean MT levels in participants on exogenous MT were significantly higher than in participants that did not use MT (p = < 0.0001). In 9 participants with very high MT levels, these dropped significantly after discontinuation of exogenous MT (p = 0.0037). In 12 participants, MT levels were significantly higher after MT therapy start compared to MT levels before MT start (p = 0.028). MT is catabolized principally by the CYP1A2 enzyme, with a half-life of about 40 min. CYP1A2 genotyping was performed in five participants with high MT levels during MT use. Although clinically suspected to be a poor CYP1A2 metabolizer, all five turned out to have haplotype CYP1A2*1F, which is associated with increased enzyme activity. This shows that genotyping of CYP1A2 is not suitable to estimate the level of CYP1A2 enzyme activity. When prescribing MT, it is strongly recommended to measure a MT level prior to treatment in order to determine the dose to be given. Checks of the MT level during treatment are necessary due to the frequent occurrence of poor CYP1A2 metabolism. Since CYP1A2 genotyping does not provide adequate information about the level of CYP1A2 enzyme activity, we propose a simple way to determine CYP1A2 phenotype.