Am J Med Genet A
· 2026 Apr · PMID 41952295
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Cases with congenital heart defects (CHD) often have other associated anomalies. The aim of this investigation was to assess the prevalence and the types of co-occurring anomalies in CHD in a well-defined population. The...Cases with congenital heart defects (CHD) often have other associated anomalies. The aim of this investigation was to assess the prevalence and the types of co-occurring anomalies in CHD in a well-defined population. The anomalies co-occurring with CHD were ascertained in all live births, stillbirths and terminations of pregnancy for fetal anomaly during 29 years in 387,067 consecutive pregnancies of known outcome in the area covered by our population-based registry of congenital anomalies. Of the 4640 cases with CHD ascertained during this period (prevalence of 119.9 per 10,000), 1228 (26.5%) had associated major anomalies. There were 410 (8.8%) cases with chromosomal abnormalities including 253 trisomies 21 (62%), and 114 (2.5%) syndromes including 23 cases with VACTERL association (24%). Seven hundred and four (15.2%) of the cases had non-syndromic, non-chromosomal multiple congenital anomalies (MCA). Anomalies in the urogenital, musculoskeletal, gastrointestinal, ear, face, and neck, and central nervous systems were the most common other anomalies. In conclusion the overall prevalence of co-occurring anomalies which was one in four cases emphasizes the need for a thorough investigation of cases with CHD. Routine screening for other anomalies may be considered in cases with CHD. One should be aware that the anomalies associated with CHD can be classified into a recognizable anomaly, chromosomal or syndromic in one out of 10 cases with CHD.
Helle K, Bengtsson JD, Gandhi M
… +8 more, Grochowski CM, Lun MY, Sudhir N, Jhangiani SN, Sedlazeck FJ, Lalani SR, Hanchard NA, Carvalho CMB
Am J Med Genet A
· 2026 Aug · PMID 41943674
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The 2q31 region is commonly associated with pathogenic alleles of the HOXD cluster leading to various clinical phenotypes related to skeletal development. We present a proband with tetralogy of Fallot and multiple congen...The 2q31 region is commonly associated with pathogenic alleles of the HOXD cluster leading to various clinical phenotypes related to skeletal development. We present a proband with tetralogy of Fallot and multiple congenital anomalies. Genomic variant screening including an in-house CGR detection pipeline pairing genome sequencing (GS) structural variant calls with read-depth data revealed a de novo complex genomic rearrangement (CGR) spanning 2.7 Mb across 2q31 characterized by a series of duplications and triplications including the HOXD gene cluster. The genomic structure was assembled by applying combined methodologies including short-read and long-read GS, and optical genome mapping (OGM). This in-house CGR pipeline detected five additional rearrangements throughout the genome confirmed by orthogonal methodologies as inherited and unlikely to impact this individual's phenotype. Importantly, these catastrophic genomic events, chromoanasynthesis-like, are surprisingly commonly observed in the genome, inherited and involve large regions of the genome. Moreover, such inherited CGRs often include copy-number gains that partially affect disease-causing genes which complicate clinical interpretation. Overall, we show the utility of short-read sequencing to uncover de novo and inherited chromoanasynthesis events and established genotype-phenotype correlation in a proband with multiple congenital malformations.
Am J Med Genet A
· 2026 Aug · PMID 41943597
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There is a strong genetic contribution to the etiology of congenital diaphragmatic hernia (CDH). This study evaluated genetic testing results and diagnostic yield for fetuses and children with CDH. This was a retrospecti...There is a strong genetic contribution to the etiology of congenital diaphragmatic hernia (CDH). This study evaluated genetic testing results and diagnostic yield for fetuses and children with CDH. This was a retrospective cohort study of exome sequencing (ES) performed at GeneDx for fetuses and children ≤ 18 years of age with CDH compared with genome sequencing (GS) from an institutional cohort. ES was available for 560 individuals (62% [n = 349] complex/syndromic; 38% [n = 211] isolated/non-syndromic) with a reportable finding identified in 61% (n = 342) overall, including 64% in complex/syndromic cases and 56% in isolated/non-syndromic cases. In the institutional cohort, GS was available for 84 individuals (19% [n = 16] complex/syndromic; 81% [n = 68] isolated/non-syndromic). In this sub-cohort, 70 individuals had variants (539 total) in genes in which variants were reported in the GeneDx cohort (234 genes). The study cohort was compared to an unrelated cohort with neural tube defects and, when evaluating 73 genes with variants present in > 1 GeneDx proband, we noted a significantly higher variant burden in the CDH cohort. Overlap of genes with variants among unrelated cohorts suggests a potential etiologic association of many known and novel CDH genes; however, additional research is needed to understand the genes' causative roles as well as the impact of non-coding and gene-environment influences on the etiology of CDH.
Williams A, Divin K, Burrage LC
… +6 more, Craigen WJ, Scaglia F, Soler-Alfonso C, Sutton VR, Glinton KE, Marom R
Am J Med Genet A
· 2026 Aug · PMID 41937280
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Benign hyperphenylalaninemia (bHPA) is defined as elevated phenylalanine (Phe) levels remaining ≤ 360 μmol/L (6 mg/dL) and not requiring medical intervention. Individuals with bHPA may demonstrate a rise in their Phe lev...Benign hyperphenylalaninemia (bHPA) is defined as elevated phenylalanine (Phe) levels remaining ≤ 360 μmol/L (6 mg/dL) and not requiring medical intervention. Individuals with bHPA may demonstrate a rise in their Phe levels > 360 μmol/L, effectively developing a mild PKU phenotype requiring therapy to prevent neurocognitive complications. This study aimed to identify risk factors for elevation of Phe > 360 μmol/L and the long-term outcome of bHPA. Retrospective chart review at a single center identified thirty-four individuals with bHPA. Among this group, twelve individuals ultimately demonstrated Phe levels > 360 μmol/L, thus defined as "Risers", as opposed to the "Non-Risers" that remained within bHPA range. Mean Phe level at first newborn screen (NBS) was higher in the Risers group. Clinical assessment pointed to developmental or behavioral issues in two-thirds of the Risers, whereas all Non-Risers had typical development. Our data suggest that bHPA may be associated with increased risk for neurodevelopmental complications among individuals who eventually developed Phe levels > 360 μmol/L. This study emphasizes that individuals with bHPA should be closely followed to track Phe levels and development.
Yilmaz SO, Yigit A, Hatipoglu S
… +7 more, Gursoy S, Gulcu A, Turhan T, Pekerbas M, Soylu A, Ozbek U, Bozkaya OG
Am J Med Genet A
· 2026 Aug · PMID 41937270
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Grange syndrome, caused by biallelic loss-of-function variants in YY1AP1, is characterized by multivascular stenoses, renovascular hypertension, brachydactyly, syndactyly, and mild cognitive impairment. Although RNF213 v...Grange syndrome, caused by biallelic loss-of-function variants in YY1AP1, is characterized by multivascular stenoses, renovascular hypertension, brachydactyly, syndactyly, and mild cognitive impairment. Although RNF213 variants are typically associated with Moyamoya disease and systemic arterial stenosis, evidence suggests that pathogenic RNF213 variants may contribute to a broader vascular phenotype. We describe a 15-year-old girl with Moyamoya vasculopathy presenting with bilateral renal artery stenosis, brachydactyly, and intellectual disability. Her history included left-arm weakness and seizures at 10 months of age. She underwent surgical revascularization at 1.5 and 3 years of age for Moyamoya disease. Upon evaluation for hypertension, the patient was diagnosed with bilateral renal artery stenosis. Physical examination revealed dysmorphic features including deep-set eyes, up slanting palpebral fissures, a broad nasal bridge, low-set, posteriorly rotated ears, a broad left thumb, brachydactyly, and syndactyly of the toes. Whole-exome sequencing was negative; trio whole-genome sequencing identified a de novo, likely pathogenic RNF213 variant (c.12341C > G). This case expands the phenotypic spectrum associated with RNF213 variants, presenting a Grange-like phenotype. Our study highlights RNF213 as a candidate gene for such phenotypes. A negative YY1AP1 result does not exclude a Grange-like phenotype, emphasizing the need for comprehensive genetic testing and early vascular surveillance.
Nisbet AF, Adams SA, Katz ZS
… +8 more, Delagrammatikas CG, Izumi K, Sigal W, Ventarola K, Zackai EH, Reid JE, Liu GT, Kalish JM
Am J Med Genet A
· 2026 Aug · PMID 41930635
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Malan syndrome is an ultra-rare overgrowth syndrome caused by pathogenic variants or deletions in nuclear factor one X (NFIX) located at 19p13.2. Here, we report a comprehensive literature review and phenotyping of known...Malan syndrome is an ultra-rare overgrowth syndrome caused by pathogenic variants or deletions in nuclear factor one X (NFIX) located at 19p13.2. Here, we report a comprehensive literature review and phenotyping of known patients with Malan syndrome and present a novel cohort of eight patients. This report further establishes the common characteristics of Malan syndrome, expands the ophthalmologic features and airway distress phenotypes, and provides updated management recommendations.
Carratu K, Crocker K, Chen S
… +3 more, Moore C, Patel NA, Krantz ID
Am J Med Genet A
· 2026 Aug · PMID 41930633
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ADNP syndrome, also known as Helsmoortel-Van der Aa syndrome, is a rare dominant syndromic neurodevelopmental diagnosis. ADNP syndrome is caused by pathogenic variants in the gene encoding the activity-dependent neuropro...ADNP syndrome, also known as Helsmoortel-Van der Aa syndrome, is a rare dominant syndromic neurodevelopmental diagnosis. ADNP syndrome is caused by pathogenic variants in the gene encoding the activity-dependent neuroprotective homeobox protein (ADNP) that plays a critical role in embryonic and postnatal hippocampal development. ADNP syndrome has a broad range of symptoms including intellectual deficits, dysmorphic features, and behavioral changes including autism spectrum disorder (ASD). Hearing loss has been reported in approximately 11.7% of individuals with ADNP syndrome. In this paper, we report the clinical findings of an individual with ADNP syndrome (c.2630_2633del; p.Asp877Valfs*36) who presents with unilateral hearing loss and confirmed ipsilateral cochlear nerve deficiency. This is the first report of cochlear nerve deficiency in an individual with ADNP syndrome and based on this review of published ADNP syndrome cases, hearing loss may be more prominent in this diagnosis than previously reported.
Lan Z, Xu B, Wang H
… +3 more, Liu S, Wang H, Zhang Z
Am J Med Genet A
· 2026 Aug · PMID 41930632
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PBX1-associated congenital anomalies of the kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay (CAKUTHED) is a highly pleiotropic, autosomal dominant developmental disor...PBX1-associated congenital anomalies of the kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay (CAKUTHED) is a highly pleiotropic, autosomal dominant developmental disorder. The disease spectrum is broad, and only a limited number of prenatal cases have been reported to date. We report two well-documented prenatal cases of CAKUTHED presenting with cardiovascular defects as the initial manifestation in the second trimester. Trio exome sequencing identified two de novo variants in PBX1 (c.192-3C>A and c.869G>A), confirming the genetic diagnosis of CAKUTHED in the two fetuses. In Case 1, minigene assays validated that the c.192-3C>A variant interfered with RNA splicing. The individual predominantly manifested tetralogy of Fallot and renal hypoplasia. In Case 2, the c.869G>A missense variant was identified, with more complex clinical features. Cardiac malformations included coarctation of the aorta, pulmonary artery stenosis, coronary sinus dilatation, and persistent left superior vena cava. Moreover, the fetus exhibited severe growth restriction, polyhydramnios, and marked thoracic and pulmonary defects, with no significant structural abnormalities of the urinary system detected. Both pregnancies were subsequently terminated. Our report, by detailing the previously rarely reported prenatal clinical features and novel genetic variants, helps to expand the known phenotypic and genotypic spectrum of PBX1-related disorders.
Gorgulu G, Akpara BB, Colak E
… +3 more, Onel E, Bolat E, Akinci G
Am J Med Genet A
· 2026 Aug · PMID 41930629
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Pathogenic variants in RALA cause Hiatt-Neu-Cooper syndrome, a rare and clinically complex neurodevelopmental condition characterized by developmental delay, hypotonia, and intellectual disability, with distinctive crani...Pathogenic variants in RALA cause Hiatt-Neu-Cooper syndrome, a rare and clinically complex neurodevelopmental condition characterized by developmental delay, hypotonia, and intellectual disability, with distinctive craniofacial features. The disease is also associated with variably occurring seizures, macrocephaly, and autism spectrum disorder. Reported manifestations have primarily involved the central nervous system, and structural spinal abnormalities have not been described to date. Here we report a child with a de novo RALA missense pathogenic variant, c.73G>A (p.Val25Met), who presented with features consistent with RALA-associated neurodevelopmental syndrome and subsequently developed progressive lower extremity weakness. Somatosensory evoked potentials were abnormal, and spinal MRI demonstrated spinal epidural lipomatosis. Surgical exploration confirmed tethered cord syndrome with a fatty filum terminale. The patient underwent surgical detethering, followed by marked postoperative improvement in motor function. This case expands the phenotypic spectrum of RALA-associated disease to include surgically treatable lumbosacral pathology. Consideration of structural spinal abnormalities may be warranted in children with RALA-related neurodevelopmental syndrome who develop new or progressive motor symptoms, as timely intervention may substantially improve functional outcomes.
Renberg A, Coppersmith S, Merritt O
… +7 more, Heider A, Helms A, Michniacki T, Luxford J, Josephi-Taylor S, Roberts P, Meisner J
Am J Med Genet A
· 2026 Aug · PMID 41928611
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Autosomal recessive loss-of-function variants in PPP1R13L cause an ultra-rare cardiocutaneous syndrome characterized by rapidly progressive arrhythmogenic cardiomyopathy (ACM). PPP1R13L encodes iASPP, which has two poten...Autosomal recessive loss-of-function variants in PPP1R13L cause an ultra-rare cardiocutaneous syndrome characterized by rapidly progressive arrhythmogenic cardiomyopathy (ACM). PPP1R13L encodes iASPP, which has two potentially overlapping mechanisms driving ACM as both a regulator of NFκB-mediated inflammation and a binding partner within the cardiac desmosome. This study explores immunotherapy and the underlying pathophysiology in two pediatric cases. Two patients (aged 47 and 32 months) with biallelic PPP1R13L variants presented with refractory ventricular arrhythmias and heart failure. Both received IL-1 blockade as adjunct therapy. Explanted heart tissue was analyzed via quantitative immunofluorescent microscopy to assess NFκβ nuclear localization and desmin localization at the intercalated disks (ID). IL-1 blockade was associated with reduced ventricular ectopy and normalized serum cytokine levels (IL-1, IL-10) but without contractile recovery. Histology analysis revealed increased NFκβ signaling only in non-cardiomyocytes but with loss of desmin at the ID in PPP1R13L cardiomyopathy compared to non-PPP1R13L dilated cardiomyopathy controls. PPP1R13L cardiomyopathy involves systemic inflammation, but loss of desmin-desmosome anchoring in cardiomyocytes appears to be the central mechanism of PPP1R13L cardiomyopathy. Targeted IL-1 blockade can be considered as adjunctive therapy for patients with PPP1R13L cardiomyopathy but further studies on treatments directed at the underlying mechanism are needed.
Yu O, Moore C, Carratu K
… +3 more, Wongkittichote P, Hong X, Frigeni M
Am J Med Genet A
· 2026 Aug · PMID 41883052
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Mucopolysaccharidosis type IIIC (MPS IIIC) is a rare lysosomal storage disorder caused by biallelic pathogenic variants in the HGSNAT gene, encoding heparan-α-glucosaminide N-acetyltransferase. Deficient enzymatic activi...Mucopolysaccharidosis type IIIC (MPS IIIC) is a rare lysosomal storage disorder caused by biallelic pathogenic variants in the HGSNAT gene, encoding heparan-α-glucosaminide N-acetyltransferase. Deficient enzymatic activity leads to heparan sulfate accumulation, resulting in progressive central nervous system involvement and multisystem disease. Clinical features typically include developmental delay, intellectual disability, behavioral disturbances, coarse facial features, hypertrichosis, and hearing loss. This report describes the oldest documented siblings with MPS IIIC: a male diagnosed at 46 years (currently 50 years) and his sister diagnosed at 38 years (currently 42 years). Both presented with bilateral sensorineural hearing loss, retinitis pigmentosa, intellectual disability, mildly coarse facial features, and hypertrichosis. Molecular analysis identified two novel HGSNAT variants: c.1205T>C; p.(Leu402Pro) and c.1565C>A; p.(Thr522Lys). Functional studies demonstrated markedly reduced heparan-α-glucosaminide N-acetyltransferase activity and elevated urinary heparan sulfate excretion, providing biochemical evidence supporting variant pathogenicity and confirming the diagnosis. These cases expand both the phenotypic and genotypic spectrum of MPS IIIC and underscore the importance of considering this disorder in adults with multisystem involvement. Functional characterization proved essential for establishing a definitive diagnosis when molecular findings alone were inconclusive.
Helderman NC, Tops CM, Legebeke J
… +13 more, Yang T, Gay MD, Terlouw D, Lashley LEELO, Aretz S, Sommer AK, Terradas M, Valle L, de Voer RM, Alexandrov LB, Morreau H, van Wezel T, Nielsen M
Am J Med Genet A
· 2026 Aug · PMID 41878782
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The Homologous Recombination Factor With OB-Fold (HROB) plays a role in homologous recombination and DNA replication, where it enhances the MCM8-MCM9 helicase complex activity. Recent findings link biallelic germline HRO...The Homologous Recombination Factor With OB-Fold (HROB) plays a role in homologous recombination and DNA replication, where it enhances the MCM8-MCM9 helicase complex activity. Recent findings link biallelic germline HROB variants to primary gonadal insufficiency (hypergonadotropic hypogonadism), a phenotype also associated with MCM8/MCM9 deficiency. Here, we describe a family where two individuals with biallelic HROB variants presented with hypergonadotropic hypogonadism and colonic polyposis. Exome sequencing identified three unique HROB variants: a likely pathogenic nonsense variant (c.1267C>T [p.(Gln423*)]) in exon four, and two missense variants (c.1363C>G [p.(Leu455Val)] and c.1318A>G [p.(Ser440Gly)]) in exon five. RNA analysis and protein mapping indicate that the nonsense variant is likely pathogenic, whereas the missense variants remain of uncertain significance. Mutational signature analysis of polyposis tissue did not reveal signatures directly linked to HROB deficiency, yet a review of published cases and analyses of cohorts with unexplained polyposis/cancer identified additional individuals with HROB variants exhibiting hypergonadotropic hypogonadism or colonic polyposis. These findings reinforce the association between biallelic germline HROB variants and hypergonadotropic hypogonadism and suggest a potential role in colonic polyposis predisposition. We recommend incorporating HROB into diagnostic gene panels for hypergonadotropic hypogonadism, especially in cases where colonic polyposis is also present. Furthermore, we emphasize the importance of additional studies to comprehensively characterize HROB's phenotypic impact and assess its contribution to disease risk.
Am J Med Genet A
· 2026 Aug · PMID 41877632
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Restrictive Dermopathy (RD, OMIM #275210) is an ultra-rare, lethal genodermatosis caused by defects in lamins and related proteins. RD is caused by biallelic pathogenic variants in ZMPSTE24, which encodes zinc metallopep...Restrictive Dermopathy (RD, OMIM #275210) is an ultra-rare, lethal genodermatosis caused by defects in lamins and related proteins. RD is caused by biallelic pathogenic variants in ZMPSTE24, which encodes zinc metallopeptidase ZMPSTE24, an enzyme essential for processing prelamin A, the precursor of lamin A. While null variants leading to a total loss of prelamin A processing have been related to neonatally lethal RD, variants preserving residual prelamin A processing function cause an allelic disorder called Mandibuloacral Dysplasia Type B (MAD-B). RD is characterized by taut translucent skin, visible superficial vessels, joint contractures, and dysmorphic features, with death usually occurring within the first month of life. Cardiac anomalies, including ASD and PDA, have been reported in a few patients, most of whom were not genetically confirmed, and transposition of the great arteries (TGA) has been described only once, also without molecular confirmation. We report a patient with restrictive dermatopathy (RD) presenting with double outlet right ventricle (DORV) and pulmonary valve atresia which have not been previously reported in association with RD. Exome Sequencing (ES) was performed, revealing a novel homozygous splice-site variant in ZMPSTE24 (c.1203 + 1G>T). Segregation analysis was performed in the mother and two siblings. To our knowledge, DORV has not previously been reported in an RD patient. This case expands the genotypic spectrum of RD and suggests a possible link with complex cardiac malformations.
Gallagher R, Aguilera A, Villarreal SA
… +8 more, Zalan A, Tomei J, Alghazzy D, Scott S, Slack N, Matter A, Broeckel U, Giampietro P
Am J Med Genet A
· 2026 Aug · PMID 41869909
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Genetic testing using targeted panels or comprehensive genome sequencing is the current standard for diagnosing Duchenne muscular dystrophy (DMD), identifying pathogenic variants in up to 98% of cases. We report a 5-year...Genetic testing using targeted panels or comprehensive genome sequencing is the current standard for diagnosing Duchenne muscular dystrophy (DMD), identifying pathogenic variants in up to 98% of cases. We report a 5-year-old male presenting with delayed motor milestones, frequent falls, and difficulty climbing stairs due to generalized muscle weakness. Laboratory studies revealed markedly elevated CK (13,041 U/L) and chronic transaminase elevation. Clinical examination demonstrated Gower's sign, calf pseudohypertrophy, neuromuscular scoliosis, and cognitive impairment. Initial neuromuscular gene panel testing identified several variants of uncertain significance, and muscle biopsy showed markedly reduced dystrophin labeling. Follow-up short-read DMD sequencing with deletion/duplication analysis at Age 11 remained negative. Given persistently negative findings, we utilized optical genome mapping (Bionano Genomics) and long-read sequencing (Oxford Nanopore Technologies) to identify potential structural variants. Both methods independently detected a novel inversion identified to span 31 kb and encompassing exons 68-73 of the DMD gene (ChrX: 31,171,362-31,202,982), classified as pathogenic. This case highlights a clinically definitive diagnosis of DMD missed by standard genetic testing. Our findings demonstrate that Optical Genome Mapping and Long-Read Sequencing provide complementary, high-resolution tools for identifying previously unidentified structural variants and should be considered in unresolved cases prior to invasive procedures such as muscle biopsy.
Turnovec M, Bubeníková A, Rýdlo O
… +8 more, Skalický P, Zápotocký M, Haratek K, Kočandrlová K, Macek M, Beneš V, Bradáč O, Havlovicová M
Am J Med Genet A
· 2026 Aug · PMID 41869744
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The AKT2-related hypoinsulinemic hypoglycemia and overgrowth syndrome was initially described over 30 years ago as MORFAN syndrome which was an acronym for Mental retardation, pre- and post-natal Overgrowth, Remarkable F...The AKT2-related hypoinsulinemic hypoglycemia and overgrowth syndrome was initially described over 30 years ago as MORFAN syndrome which was an acronym for Mental retardation, pre- and post-natal Overgrowth, Remarkable Face, and Acanthosis Nigricans. Despite the limited possibility of confirming a diagnosis on the molecular level at that time, a comprehensive 30-year follow-up of a patient facilitated a detailed exploration of the syndrome's clinical trajectory. This article presents a case report spanning three decades, highlighting the significance of detailed clinical follow-up in understanding and studying this unique syndrome. Although initially associated with intellectual deficiency, the patient's intellectual abilities remain largely within the normal range. Neuropsychological examinations revealed selective neurocognitive impairment, with a predominant disruption in psychomotor speed and executive functions. Molecular genetic examination confirmed a pathogenic variant in the AKT2 gene, associated with impaired insulin metabolism and increased tumorigenesis risk. Neurooncological assessments revealed intracranial meningiomatosis, emphasizing the syndrome's potential oncological implications. Surgical interventions addressed various complications, including meningiomas and renal hamartomas. The presented case offers valuable insights into the long-term natural history of AKT2-related hypoinsulinemic hypoglycemia and overgrowth syndrome, suggesting the importance of regular oncological surveillance due to its predisposition to tumorigenesis, thereby providing clinical considerations for future cases based on long-term follow-up experience.
Villeneuve-Cloutier N, Warman-Chardon J, Bourque DK
Am J Med Genet A
· 2026 Aug · PMID 41866827
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Combined oxidative phosphorylation deficiency 4 (COXPD4) is a rare mitochondrial condition caused by biallelic deleterious variants in the nuclear-encoded gene TUFM. To date, most individuals with COXPD4 have presented w...Combined oxidative phosphorylation deficiency 4 (COXPD4) is a rare mitochondrial condition caused by biallelic deleterious variants in the nuclear-encoded gene TUFM. To date, most individuals with COXPD4 have presented with encephalopathy, hypotonia, and abnormal brain imaging. Many of the reported individuals died in infancy. We aim to expand the clinical and biochemical phenotype of COXPD4 by reporting on an adult with this condition. Our proband has a homozygous TUFM c.1025T>G, p.(Val342Gly) variant. He has sensorineural hearing loss, hyperlactatemia with mild illness, and reduced activity in mitochondrial complexes I, III, and IV on endomyocardial biopsy. He presents with hypertrophic cardiomyopathy and chronic kidney failure, which have not previously been reported in this condition. Our findings suggest not all individuals with COXPD4 present with significant neurological involvement and highlight the importance of considering COXPD4 as part of the differential diagnosis of hypertrophic cardiomyopathy.
Carter C, Luz D, Smith EE
… +4 more, Scott SA, Srinivas NS, Shi RZ, Tise CG
Am J Med Genet A
· 2026 Aug · PMID 41866816
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Transient neonatal zinc deficiency (TNZD) is a genetic condition that presents with dermatitis, alopecia, diarrhea, and growth faltering in breast milk-fed infants of females with a heterozygous pathogenic variant in SLC...Transient neonatal zinc deficiency (TNZD) is a genetic condition that presents with dermatitis, alopecia, diarrhea, and growth faltering in breast milk-fed infants of females with a heterozygous pathogenic variant in SLC30A2, the primary zinc transporter in mammary glands. Despite being an easily treatable condition, effectively evaluating for TNZD can be challenging because the infant's genotype does not reliably reflect the mother's genotype. Herein, we present our approach to diagnosis in an exclusively breastfed 5-month-old infant with treatment-refractory eczematous rash, admitted for growth faltering and decreased serum zinc and alkaline phosphatase levels. The infant was diagnosed with TNZD via trio genome-based exome sequencing after a heterozygous SLC30A2 variant of uncertain significance (VUS) (c.927G>C; p.Trp309Cys) was identified in the proband's mother, which was notably absent in the proband. Breast milk zinc concentration ([Zn]) was measured in duplicate via inductively coupled mass spectrometry in 10 samples (3 from the proband's mother and 7 from unrelated controls) and measured -265, -144, and -46 μg/dL below expected [Zn] at 0, 5, and 7 months postpartum, respectively, compared to an average deviation of -29 μg/dL in controls. Zinc supplementation in the infant led to rapid clinical improvement. The absence of the maternal SLC30A2 variant in the proband underscores diagnostic challenges in evaluating for TNZD, as primary variant analysis is typically limited to the proband in trio testing. Though the prevalence of SLC30A2 disease-causing variants is unclear, carrier screening may provide a unique opportunity to proactively identify females with known pathogenic SLC30A2 variants that would impart risk to their future breastfed children and breast milk recipients.
Valle T, Damián A, Torres M
… +16 more, Méndez P, Márquez A, Cazalla M, Jiménez-Estrada JA, Rodríguez-Canó M, Gallego-Zazo N, Vásquez-Amell V, Miranda Alcaraz L, Mora-Gómez M, Ruiz Pérez VL, Nevado J, Tenorio-Castaño J, Morte B, Carracedo Á, Lapunzina P, Galán E
Am J Med Genet A
· 2026 Aug · PMID 41866812
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We report a 5-year-old Spanish male with a homozygous SPOUT1 variant (NM_016390.4:c.1058C>T; p.Thr353Met), identified by re-analysis of whole-genome sequencing. His phenotype includes severe developmental delay, microcep...We report a 5-year-old Spanish male with a homozygous SPOUT1 variant (NM_016390.4:c.1058C>T; p.Thr353Met), identified by re-analysis of whole-genome sequencing. His phenotype includes severe developmental delay, microcephaly, epilepsy evolving to Lennox-Gastaut-like syndrome, growth impairment, dysmorphic features, and multiple congenital anomalies. Our case expands the SPOUT1-related neurodevelopmental spectrum and underscores the diagnostic value of periodic genomic data re-analysis.