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Background Primary hereditary microcephaly (MCPH) comprises a large group of autosomal recessive disorders mainly affecting cortical development and resulting in a congenital impairment of brain growth. Despite the identification of >25 causal genes so far, it remains a challenge to distinguish between different MCPH forms at the clinical level. Methods 7 patients with newly identified mutations in CDK5RAP2 (MCPH3) were investigated by performing prospective, extensive and systematic clinical, MRI, psychomotor, neurosensory and cognitive examinations under similar conditions. Results All patients displayed neurosensory defects in addition to microcephaly. Small cochlea with incomplete partition type II was found in all cases and was associated with progressive deafness in 4 of them. Furthermore, the CDK5RAP2 protein was specifically identified in the developing cochlea from human fetal tissues. Microphthalmia was also present in all patients along with retinal pigmentation changes and lipofuscin deposits. Finally, hypothalamic anomalies consisting of interhypothalamic adhesions, a congenital midline defect usually associated with holoprosencephaly, was detected in 5 cases. Conclusion This is the first report indicating that CDK5RAP2 not only governs brain size but also plays a role in ocular and cochlear development and is necessary for hypothalamic nuclear separation at the midline. Our data indicate that CDK5RAP2 should be considered as a potential gene associated with deafness and forme fruste of holoprosencephaly. These children should be given neurosensory follow-up to prevent additional comorbidities and allow them reaching their full educational potential. [ABSTRACT FROM AUTHOR]

Background: Arthrogryposis multiplex congenita (AMC) is characterised by congenital joint contractures in two or more body areas. AMC exhibits wide phenotypic and genetic heterogeneity. Our goals were to improve the genetic diagnosis rates of AMC, to evaluate the added value of whole exome sequencing (WES) compared with targeted exome sequencing (TES) and to identify new genes in 315 unrelated undiagnosed AMC families., Methods: Several genomic approaches were used including genetic mapping of disease loci in multiplex or consanguineous families, TES then WES. Sanger sequencing was performed to identify or validate variants., Results: We achieved disease gene identification in 52.7% of AMC index patients including nine recently identified genes ( CNTNAP1 , MAGEL2 , ADGRG6 , ADCY6 , GLDN , LGI4 , LMOD3 , UNC50 and SCN1A ). Moreover, we identified pathogenic variants in ASXL3 and STAC3 expanding the phenotypes associated with these genes. The most frequent cause of AMC was a primary involvement of skeletal muscle (40%) followed by brain (22%). The most frequent mode of inheritance is autosomal recessive (66.3% of patients). In sporadic patients born to non-consanguineous parents (n=60), de novo dominant autosomal or X linked variants were observed in 30 of them (50%)., Conclusion: New genes recently identified in AMC represent 21% of causing genes in our cohort. A high proportion of de novo variants were observed indicating that this mechanism plays a prominent part in this developmental disease. Our data showed the added value of WES when compared with TES due to the larger clinical spectrum of some disease genes than initially described and the identification of novel genes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

EFEMP2 mutations are known to be responsible for autosomal recessive cutis laxa type 1B (ARCL1B), a rare multisystem disease affecting skin, skeleton, and vascular structures. We report 2 additional related cases of ARCL1B of particular severity leading to termination of pregnancy. Cardinal signs of this connective tissue disease were already seen during the second trimester of pregnancy, then confirmed and clarified at autopsy. Anomalies included cutis laxa, arachnodactyly, clubfoot, wormian bones, moderate bowing of long bones with slender bone trabeculae, rib fractures, undermuscularized diaphragm, hiatal hernia, and arterial tortuosity with thick vascular walls and disorganized elastic fibers. Sequencing of the EFEMP2 gene revealed a novel homozygous nonsense mutation: c.639C>A (p.Cys213*). We performed a thorough histological analysis and discuss differential diagnoses, genotype-phenotype correlations, and the challenge of prenatal diagnosis of this disease.