Albert de la Chapelle

Albert Fredrik de la Chapelle, MD, Ph.D (11 February 1933 – 10 December 2020) was a Finnish human geneticist, long-time head of Finland's first Department of Medical Genetics at the University of Helsinki, and subsequently professor of Human Cancer Genetics at Ohio State University.

He was best known for his role in the elucidation of the genetics of hereditary colorectal cancer and Lynch syndrome.

Albert de la Chapelle was born in 1933, Helsinki, one of three sons (along with Claës-Henrik and Gustaf) of Claës Carl Fredrik René de la Chapelle (1900–1974) and Stina Serlachius (1902–1984).

He spent his early childhood on his parents' apple growing estate.

He attended school locally, transferring later to high school in Helsinki.

Graduating from high school in 1950 he enrolled directly into medical school at the University of Helsinki, obtaining his MD in 1957 after a hiatus to complete 11 months of military service resulting in the rank of lieutenant.

De la Chapelle was in clinical training in Endocrinology when a paper appeared in 1959 describing the loss of an X chromosome (45,X) in Turner's syndrome.

He founded the first human cytogenetics laboratory in Finland and at first concentrated on the cytogenetics of Turner's syndrome.

It turned out that in addition to 45,X, structural abnormalities of the single X chromosome were commonly involved, as well as mosaicism.

Genotype/phenotype correlations were described.

The resulting publication became de la Chapelle's first breakthrough publication and also his Ph.D. thesis on the cytogenetics in Turner syndrome; at that time it was the most extensive study in the field.

Targeting abnormalities affecting sex determination, de la Chapelle published the first example of a male with the karyotype 46,XX.

This was the first step towards the establishment of the XX male syndrome.

It is now referred to by OMIM as 46,XX sex reversal 1, abbreviated SRXX1, OMIM #400045 ( http://omim.org ).

Obviously XX males might provide valuable insight into sex determination genes and mechanisms that were unknown at the time.

He then worked on his PhD graduating from the University of Helsinki in 1962.

He was board certified in internal medicine and clinical genetics in Finland.

De la Chapelle was married to Clara D. Bloomfield.

De la Chapelle worked with Finnish, French and US geneticists to solve the mystery of maleness without a Y. In the period between 1964 and 1990 he authored 45 peer-reviewed articles on the subject of sex determination.

In the end it was detected (i) that the X and Y chromosomes share a tiny pseudoautosomal region that pairs and recombines in meiosis, (ii) that most XX males arise as a consequence of accidental unequal recombination in the paternal meiosis, transferring the male-determining region from the Y to the X). Soon after this discovery, the male determining gene SRY was cloned (by others).

De la Chapelle worked for two years in the biochemistry lab of Dr. Paul Marks at Columbia University, New York, 1966–1968; for a semester in the Blood Group Unit of Ruth Sanger and Rob Race at the University of London 1974, and a year in the molecular genetics lab of Dr. Jean-Claude Kaplan at the University of Paris 1981–82.

In 1972 a rare novel recessively inherited lethal skeletal dysplasia characterized by extreme micromelia (short limbs) was described.

The underlying mutation, homozygosity for p.T512K in the SLC26A2 gene was later found to be responsible for the syndrome.

The syndrome is called "de la Chapelle dysplasia" (DLCD; OMIM #256050).

An alternative name is Atelosteogenesis type 2.

De la Chapelle decided to begin to clarify the genetic basis of some 30 disorders (most recessively inherited) that were known to be greatly over-represented in the Finnish population due to its founder nature, i.e., the present population derives from a small number of settlers without significant recent influx.

The diseases are said to comprise the "Finnish Disease Heritage".

The de la Chapelle laboratory soon was transformed into a molecular genetics one working mainly with restriction fragment length polymorphisms as markers.

Prominent use of the strong linkage disequilibrium patterns was an important tool.

Disease after disease was mapped to critical genomic intervals.

By positional cloning the culpable genes were identified based on the occurrence of pathogenic mutations.

The number of diseases studied is approximately 24, including a few "non-Finnish" disorders such as Peutz–Jeghers syndrome, and a few in which the de la Chapelle group mapped the region but the gene was found by others.

He held Finland's first Chair in Medical Genetics at the University of Helsinki between 1974 and 1997, when he moved to Ohio State University with the aim of building a Human Cancer Genetics Program.

He held a chair in Human Cancer Genetics in the program which comprises greater than 20 faculty and greater than 200 total personnel.

De la Chapelle was married to Dr. Clara D. Bloomfield, an expert on leukemia.

These extensive findings were published between approximately 1987 (Choroideremia, a "Finnish" disorder), and 2011 (MOPD1 disease in the Ohio Amish).

Dr. Henry Lynch's name is attached to a condition, Lynch Syndrome (formerly Hereditary Nonpolyposis Colorectal Cancer, HNPCC), characterized by a greatly increased risk of colorectal and endometrial cancer, plus a moderately increased risk of ~7 other cancers.

In 1992 collaborations between Finnish, US, New Zealand and Canadian researchers had led to the study of 2 exceptionally large families favorable for linkage analysis.

Genotyping these in Helsinki led to a breakthrough; convincing linkage was found to a locus on chromosome 2p which was subsequently shown to harbor the MSH2 gene.

This for the first time proved that Lynch syndrome exists as a Mendelian disorder.