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<p>The phenotypic similarities and genetic heterogeneity occurring in diverse forms of Ehlers Danlos Syndrome (EDS) subtypes and many heritable connective tissue disorders can pose a diagnostic challenge. In the wake of the growing applications of next‐generation sequencing technologies including exome and genome sequencing, opportunities for achieving definitive genetic diagnosis are increasingly arising. We present a 46-year-old man with joint laxity, recurrent joint subluxations, pelvic floor dysfunction, and postural orthostatic tachycardia syndrome (POTS), who was referred for EDS assessment. His medical history included morbid obesity requiring gastric bypass surgery,&#xa0;hearing loss, asthma, retinopathy,&#xa0;myopia, atrial septal defect, narcolepsy&#xa0;with&#xa0;cataplexy, polyneuropathy, folliculitis, lichen&#xa0;simplex&#xa0;chronicus, atopic&#xa0;dermatitis,&#xa0;and&#xa0;hypogonadism. His family history was significant for multiple first- and second-degree relatives who died from cardiac diseases including cases of childhood deaths. Physical examination showed joint laxity with Beighton score of 3/9, bilateral pes planus, hearing loss and macrocephaly. Exome sequencing revealed heterozygous variants <i>LMNA</i> c.1262&#xa0;T &gt; C p.L421P [classified as likely pathogenic], <i>FLG</i> c.2282_2285del p. S761Cfs*36 [classified as pathogenic], and <i>FLG</i> c.1501 C &gt; T p. R501* [classified as pathogenic]. Mitochondria&#xa0;sequencing&#xa0;revealed a variant of uncertain significance (VUS), MT-ND2 m.5047&#xa0;T &gt; C p.V193A that is present at 9% heteroplasmy in blood. These findings show co-occurrence of pathogenic sequence variants in neighboring genes located in chromosome 1q2 region [<i>LMNA</i> and <i>FLG</i>] in a patient with features of hereditary connective tissue disorders. Our study highlights the capability of exome sequencing in achieving some actionable diagnosis in cases of co-morbid genetic disorders with overlapping and non-specific symptoms.</p>

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Co-morbid monogenic disorders at chromosome region 1q2: LMNA- and FLG-related disorders in a patient referred for assessment of joint hypermobility

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  • 发表日期：

    2025年10月30日

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  • Mayowa A. Osundiji,
  • Adedamola O. Bello,
  • Jennifer L. Hand

摘要

The phenotypic similarities and genetic heterogeneity occurring in diverse forms of Ehlers Danlos Syndrome (EDS) subtypes and many heritable connective tissue disorders can pose a diagnostic challenge. In the wake of the growing applications of next‐generation sequencing technologies including exome and genome sequencing, opportunities for achieving definitive genetic diagnosis are increasingly arising. We present a 46-year-old man with joint laxity, recurrent joint subluxations, pelvic floor dysfunction, and postural orthostatic tachycardia syndrome (POTS), who was referred for EDS assessment. His medical history included morbid obesity requiring gastric bypass surgery, hearing loss, asthma, retinopathy, myopia, atrial septal defect, narcolepsy with cataplexy, polyneuropathy, folliculitis, lichen simplex chronicus, atopic dermatitis, and hypogonadism. His family history was significant for multiple first- and second-degree relatives who died from cardiac diseases including cases of childhood deaths. Physical examination showed joint laxity with Beighton score of 3/9, bilateral pes planus, hearing loss and macrocephaly. Exome sequencing revealed heterozygous variants LMNA c.1262 T > C p.L421P [classified as likely pathogenic], FLG c.2282_2285del p. S761Cfs*36 [classified as pathogenic], and FLG c.1501 C > T p. R501* [classified as pathogenic]. Mitochondria sequencing revealed a variant of uncertain significance (VUS), MT-ND2 m.5047 T > C p.V193A that is present at 9% heteroplasmy in blood. These findings show co-occurrence of pathogenic sequence variants in neighboring genes located in chromosome 1q2 region [LMNA and FLG] in a patient with features of hereditary connective tissue disorders. Our study highlights the capability of exome sequencing in achieving some actionable diagnosis in cases of co-morbid genetic disorders with overlapping and non-specific symptoms.