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Cornelia de Lange syndrome (CdLS) is a rare congenital developmental disorder with multisystemic involvement. The clinical presentation is highly variable, but the classic phenotype, characterized by distinctive craniofacial features, pre- and postnatal growth retardation, extremity reduction defects, hirsutism and intellectual disability can be distinguished from the nonclassic phenotype, which is generally milder and more difficult to diagnose. In addition, the clinical features overlap with those of other neurodevelopmental disorders, so the use of consensus clinical criteria and artificial intelligence tools may be helpful in confirming the diagnosis.Pathogenic variants in NIPBL, which encodes a protein related to the cohesin complex, have been identified in more than 60% of patients, and pathogenic variants in other genes related to this complex in another 15%: SMC1A, SMC3, RAD21, and HDAC8. Technical advances in large-scale sequencing have allowed the description of additional genes (BRD4, ANKRD11, MAU2), but the lack of molecular diagnosis in 15% of individuals and the substantial clinical heterogeneity of the syndrome suggest that other genes and mechanisms may be involved.Although there is no curative treatment, there are symptomatic/palliative treatments that paediatricians should be aware of. The main medical complication in classic SCdL is gastro-esophageal reflux (GER), which should be treated early. Resumen: El síndrome de Cornelia de Lange (SCdL) es un raro trastorno congénito del desarrollo de afectación multisistémica. Las manifestaciones clínicas son muy variables, pero se distingue entre un fenotipo clásico, caracterizado por unos rasgos craneofaciales distintivos, retraso del crecimiento pre y postnatal, defectos por reducción de las extremidades, hirsutismo y discapacidad intelectual y un fenotipo no clásico, generalmente más leve y más difícil de diagnosticar. Además, las características clínicas se superponen con las de otros desordenes del neurodesarrollo, por lo que la utilización de criterios clínicos consensuados y herramientas de inteligencia artificial pueden ser útiles para confirmar el diagnóstico.En más del 60% de los pacientes se han identificado variantes patogénicas en el gen NIPBL, que codifica una proteína relacionada con el complejo de la cohesina, y en otro 15% en 4 genes también asociados a este complejo: SMC1A, SMC3, RAD21 y HDAC8. Los progresos técnicos en las técnicas de secuenciación masiva han permitido describir otros genes relacionados (BRD4, ANKRD11 y MAU2), pero la ausencia de diagnóstico molecular en el 15% de los casos y la gran heterogeneidad clínica del síndrome, sugiere la existencia de otros genes y mecanismos relacionados.Aunque no haya un tratamiento curativo, sí hay tratamientos sintomáticos/paliativos que deben ser conocidos por el pediatra. La principal complicación médica en el SCdL clásico es el reflujo gastroesofágico (RGE), que debe ser tratado de forma precoz y contundente, ya que es una de las causas más frecuentes de fallecimiento en estos pacientes.

Summary: The NIPBL/MAU2 heterodimer loads cohesin onto chromatin. Mutations in NIPBL account for most cases of the rare developmental disorder Cornelia de Lange syndrome (CdLS). Here we report a MAU2 variant causing CdLS, a deletion of seven amino acids that impairs the interaction between MAU2 and the NIPBL N terminus. Investigating this interaction, we discovered that MAU2 and the NIPBL N terminus are largely dispensable for normal cohesin and NIPBL function in cells with a NIPBL early truncating mutation. Despite a predicted fatal outcome of an out-of-frame single nucleotide duplication in NIPBL, engineered in two different cell lines, alternative translation initiation yields a form of NIPBL missing N-terminal residues. This form cannot interact with MAU2, but binds DNA and mediates cohesin loading. Altogether, our work reveals that cohesin loading can occur independently of functional NIPBL/MAU2 complexes and highlights a novel mechanism protective against out-of-frame mutations that is potentially relevant for other genetic conditions.

A novel lyase activity enzyme is characterized for the first time: HMG-CoA lyase-like1 (er-cHL), which is a close homolog of mitochondrial HMG-CoA lyase (mHL). Initial data show that there are nine mature transcripts for the novel gene HMGCLL1, although none of them has all its exons. The most abundant transcript is called “variant b,” and it lacks exons 2 and 3. Moreover, a three-dimensional model of the novel enzyme is proposed. Colocalization studies show a dual location of the er-cHL in the endoplasmic reticulum (ER) and cytosol, but not in mitochondria or peroxisomes. Furthermore, the dissociation experiment suggests that it is a nonendoplasmic reticulum integral membrane protein. The kinetic parameters of er-cHL indicate that it has a lower Vmax and a higher substrate affinity than mHL. Protein expression and lyase activity were found in several tissues, and were particularly strong in lung and kidney. The occurrence of er-cHL in brain is surprising, as mHL has not been found there. Although mHL activity is clearly associated with energy metabolism, the results suggest that er-cHL is more closely related to another metabolic function, mostly at the pulmonary and brain level.